Heterocyclic boronic acid compounds

ABSTRACT

Dipeptidyl peptidase IV (DPP-IV)-inhibiting compounds are provided that have formula I: wherein n is 1 to 3; X is CH 2;  S; O; CF 2  or C(CH 2 ) 2 ; Z is H; halogen; hydroxyl; (C 1-6 )alkoxy; (C 1-12 )alkyl; (C 3-12 )cycloalkyl; phenyl; or heteroaryl; where the phenyl and heteroaryl groups are optionally mono- or independently plurisubstituted with R7; optionally, X together with an adjacent ring carbon and Z form a fused cyclopropyl; and optionally, one of the bonds in the ring containing X is a double bond; and Cr i R ii , R 1 , R 1 , R 3 , R 4  and R 5  are as described herein. Methods for preparing these compounds, and methods for treating diabetes, especially Type II diabetes, and other related diseases are described using the compounds of formula I in pharmaceutical compositions which contain these compounds. Pharmaceutical compositions which contain combinations of these compounds with other antidiabetic agents are also described herein.

FIELD OF THE INVENTION

The present invention relates to boronic acid compounds and their use asinhibitors of post-proline/alanine cleaving amino-dipeptidases. Theinvention also relates to methods of employing such inhibitors, alone orwith another therapeutic agent, to treating DPP-IV-related diseases,such as Type II diabetes and diabetic complications, hyperglycemia,Syndrome X, hyperinsulinemia, obesity, atherosclerosis and relateddiseases, as well as various immunomodulatory diseases and chronicinflammatory bowel disease. Thus, the invention has applications in themedicinal chemical, pharmacological, and medical arts.

BACKGROUND OF THE INVENTION

The following background commentary is an aid to in understanding thepresent invention. Inclusion of this commentary is not an admissionconcerning the nature or content of the prior art.

Dipeptidyl peptidase-IV (DPP-IV) is a serine protease that belongs to agroup of post-proline/alanine cleaving amino-dipeptidases. DPP-IVcatalyzes the release of an N-terminal dipeptide only from proteins withN-terminal penultimate proline or alanine.

The physiological role of DPP-IV has not been established fully. It isbelieved to play an important role in neuropeptide metabolism, T-cellactivation, gastric ulceration, functional dyspepsia, obesity, appetiteregulation, impaired fasting glucose (IFG), and diabetes. In particular,DPP-IV has been implicated in the control of glucose metabolism becauseits substrates include the insulinotropic hormones, glucagon likepeptide-1 (GLP-1) and gastric inhibitory peptide (GIP), which areinactivated by removal of their two N-terminal amino acids.

In vivo administration of synthetic inhibitors of DPP-IV preventsN-terminal degradation of GLP-1 and GIP, resulting in higher plasmaconcentrations of these hormones, increased insulin secretion and,therefore, improved glucose tolerance. Therefore, such inhibitors havebeen proposed for the treatment of patients with type II diabetes, adisease characterized by decreased glucose tolerance and insulinresistance.

Post-proline/alanine cleaving amino-dipeptidases have been discovered,including DPP7, DPP8, DPP9, and fibroblast activation protein (FAP),that have the substrate- and inhibitor-specificity of DPP-IV. Thus,inhibitors of this sort may affect multiple members of the enzyme group.The precise physiological role of each of these post-proline/alaninecleaving enzymes is not well defined. Consequently, inhibiting each ofthem separately, a subset of them, or all of them at the same time wouldhave uncertain physiological effect(s).

Diabetic dyslipidemia is characterized by multiple lipoprotein defects,including moderately high serum levels of cholesterol and triglycerides,small LDL particles, and low levels of HDL cholesterol. The results ofrecent clinical trials reveal beneficial effects of cholesterol-loweringtherapy in diabetic and nondiabetic patients, thus supporting increasedemphasis on treatment of diabetic dyslipidemia. This need for intensivetreatment of diabetic dyslipidemia was advocated by the NationalCholesterol Education Program's Adult Treatment Panel III.

Obesity is a well-known risk factor for the development of many verycommon diseases such as atherosclerosis, hypertension and diabetes. Theincidence of obese people and thereby also these diseases is increasingthroughout the entire industrialized world. Except for exercise, dietand food restriction no convincing pharmacological treatment forreducing body weight effectively and acceptably currently exist.However, due to its indirect but important effect as a risk factor inmortal and common diseases it will be important to find treatment forobesity or appetite regulation. Even mild obesity increases the risk forpremature death, diabetes, hypertension, atherosclerosis, gallbladderdisease and certain types of cancer. In the industrialized western worldthe prevalence of obesity has increased significantly in the past fewdecades. Because of the high prevalence of obesity and its healthconsequences, its prevention and treatment should be a high publichealth priority.

At present a variety of techniques are available to effect initialweight loss. Unfortunately, initial weight loss is not an optimaltherapeutic goal. Rather, the problem is that most obese patientseventually regain their weight. An effective means to establish and/orsustain weight loss is the major challenge in the treatment of obesitytoday.

Accordingly, a need exists for compounds that are useful for inhibitingDPP-IV without suppressing the immune system.

Several compounds have been shown to inhibit DPP-IV, but all of thesehave limitations in relation to the potency, stability, selectivity,toxicity, and/or pharmacodynamic properties. Such compounds have beendisclosed, for example, in WO 98/19998, WO 00/34241, U.S. Pat. No.6,124,305 (Novartis AG), and WO 99/38501 (Trustees of Tufts University).

SUMMARY OF THE INVENTION

The present invention provides DPP-IV inhibitors that are effective intreating conditions that may be regulated or normalized by inhibition ofDPP-IV. More particularly, the invention relates to boronicacid-containing heterocycles and their derivatives that inhibit DPP-IV,and to methods for making such compounds. In addition, the inventionprovides pharmaceutical compositions comprising compounds of theinvention, and combinations thereof including one or more other types ofantidiabetic agents; methods for inhibiting DPP-IV comprisingadministering to a patient in need of such treatment a therapeuticallyeffective amount thereof; and compounds for use as a pharmaceutical, andtheir use in a process for the preparation of a medicament for treatinga condition that are regulated or normalized via inhibition of DPP-IV.

BRIEF DESCRIPTION OF THE DRAWING

FIG. 1 shows the pH dependence of the percentage of linear and cyclicisomeric forms present in aqueous solution of a compound of theinvention.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides compounds of formula I:

including all enantiomers, diastereoisomers, solvates, hydrates andpharmaceutically acceptable salts thereof, wherein:

n is 1 to 3;

X is CH₂; S; O; CF₂ or C(CH₃)₂;

Z is H; halogen; hydroxyl; (C₁₋₆)alkoxy; (C₁₋₁₂)alkyl;(C₃₋₁₂)cycloalkyl; phenyl; or heteroaryl; where the phenyl andheteroaryl groups are optionally mono- or independently plurisubstitutedwith R⁷;

optionally, X together with an adjacent ring carbon and Z form a fusedcyclopropyl; and

optionally, one of the bonds in the ring containing X is a double bond;

R¹ and R² independently or together are hydrogen; a boronic acidprotecting group; or a group capable of being hydrolyzed to a hydroxylgroup in an aqueous solution at physiological pH or in biologicalfluids;

CR^(i)R^(ii) may be present or absent, wherein if CR^(i)R^(ii) ispresent, then R^(i), R^(ii), R³, R⁴ and R⁵ are selected from (aa), (bb)or (cc):

-   -   (aa) R^(i), R^(ii), R³ and R⁴ are hydrogen; and        -   R⁵ is            -   a) hydrogen;            -   b) (C₁₋₁₂)alkyl; (C₂₋₁₂)alkenyl; (C₂₋₁₂)alkynyl; (C₃₋₁₂)                cycloalkyl; or (C₃₋₁₂)cycloalkenyl; where the alkyl,                alkenyl, alkynyl, cycloalkyl and cycloalkenyl groups are                optionally mono- or independently plurisubstituted with                R⁶, and where the alkyl, alkenyl, alkynyl portions                include linear or branched chains and may include cyclic                portions;            -   R⁶ is (C₁₋₆)alkyl; (C₁₋₆)alkoxy; cycloalkyl; carboxy;                acetamido; cyano; nitro; halogen; hydroxy;                hydroxy(C₁₋₆)alkyl; hydroxymethyl; trifluoromethyl;                trifluoromethoxy; sulfamoyl; sulfonamido; carbamoyl;                aryl; heteroaryl; where the aryl and heteroaryl groups                are optionally mono- or independently plurisubstituted                with R⁷; amino, where the amino group is optionally                mono- or independently plurisubstituted with R⁸; —SOR⁸;                —SO₂R⁸; —COR⁸; —CO₂R⁸, —CONHR⁸; —CON(R⁸)₂; —OR⁸; or                —S—R⁸;            -   R⁷ is halogen; (C₁₋₁₀)alkyl; (C₁₋₁₀)alkoxy;                (C₁₋₁₀)alkylamino; (C₁₋₁₀)dialkylamino; benzyl;                benzyloxy; hydroxyl(C₁₋₆)alkyl; hydroxymethyl; nitro;                trifluoromethyl; trifluoromethoxy; trifluoromethylthio;                N-hydroxyimino; cyano; carboxy; acetamido; hydroxy;                sulfamoyl; sulfonamido; or carbamoyl;            -   R⁸ is (C₁₋₁₀)alkyl; (C₂₋₁₀)alkenyl; (C₂₋₁₀)alkynyl;                (C₃₋₁₀)cycloalkyl; (C₅₋₁₀)cycloalkenyl; benzyl;                phenethyl; aryl; or heteroaryl; where the alkyl,                alkenyl, alkynyl, cycloalkyl, cycloalkenyl groups are                optionally mono- or independently plurisubstituted with                aryl or heteroaryl where the aryl and heteroaryl groups                are optionally mono- or independently plurisubstituted                with R⁷; and where the aryl and heteroaryl groups are                optionally mono- or independently plurisubstituted with                R⁷;            -   c) aryl optionally fused to a (C₃₋₁₀)cycloalkyl; or                heteroaryl optionally fused to a (C₃₋₁₀)cycloalkyl;                where the aryl and heteroaryl groups are optionally                mono- or independently plurisubstituted with R⁷;            -   d) indanyl; 1,2,3,4-tetrahydronaphthyl;                (CH₂)_(j)adamantyl in which j is 0-3; or a [2.2.1] or                [3.1.1] bicyclic carbocyclic moiety, including                (4-pentylbicyclo[2.2.2]oct-1-yl)amine; where the                indanyl, 1,2,3,4-tetrahydronaphthyl, (CH₂)_(j)adamantyl,                and [2.2.1] or [3.1.1] bicyclic carbocyclic moieties are                optionally mono- or independently plurisubstituted with                hydroxy, (C₁₋₈)alkoxy, (C₁₋₈)alkanoyloxy, or                R⁹R¹⁰N—CO—O—, where R⁹ and R¹⁰ are independently                (C₁₋₈)alkyl, or phenyl, where the alkyl and phenyl                groups are optionally mono- or independently                plurisubstituted with (C₁₋₈)alkyl, (C₁₋₈)alkoxy,                halogen, or trifluoromethyl, or R⁹ and R¹⁰ together are                (C₃₋₆)alkylene;            -   e) R¹¹(CH₂)_(p)— where R¹¹ is 2-oxopyrrolidinyl;                (C₁₋₆)alkoxy; phenyl; phenoxy; (C₁₋₈)cycloalkyl; [3.3.3]                bicyclic carbocyclic moiety; pyridinyl; naphthyl;                cyclohexenyl; or adamantyl; where the 2-oxopyrrolidinyl,                (C₁₋₆)alkoxy, phenyl, pyridinyl, and naphthyl groups are                optionally mono- or independently di- or independently                trisubstituted with R¹²; where the phenoxy group is                optionally mono- or independently disubstituted with                (C₁₋₄)alkyl, (C₁₋₄)alkoxy, or halogen; and where the                [3.3.3] bicyclic carbocyclic moiety is optionally                mono-or independently plurisubstituted with (C₁₋₈)alkyl;                and p is 0 to 3;            -   R¹² is halogen; trifluoromethyl; cyano; nitro;                (C₁₋₆)alkyl; (C₁₋₆)alkoxy; cycloalkyl; carboxy;                acetamido; hydroxy; hydroxy(C₁₋₆)alkyl; hydroxymethyl;                trifluoromethoxy; sulfamoyl; carbamoyl; sulfonamido;                alkylsufonyl; phenylsulfonyl; aryl; heteroaryl; where                the aryl and heteroaryl groups are optionally mono- or                independently plurisubstituted with R⁷;            -   f) (R¹³)₂CH(CH₂)_(q)—, where R¹³ is phenyl; in which the                phenyl groups are independently optionally mono- or                independently disubstituted with R¹²; and q is 0 to 3;            -   g) a group of the formula:

where R¹⁴ and R¹⁵ are independently hydrogen; (C₁₋₈)alkyl;(C₁₋₆)alkylcarbonyl; (C₃₋₁₂)cycloalkyl ring; (C₃₋₁₂)cycloalkenyl ring;benzyl; benzoyl; pyridine; pyrimidine; phenyl; phenylamino-carbonyl;alkylsulfonyl; or phenylsulfonyl; where the cycloalkyl ring isoptionally substituted with hydroxy(C₁₋₆)alkyl, and where the benzyl,benzoyl, pyridine, pyrimidine, phenyl, phenylaminocarbonyl,alkylsulfonyl, and phenylsulfonyl groups are optionally mono- orindependently di-substituted with R¹²; or R¹⁴ and R¹⁵ together form a(C₃₋₁₂)cycloalkyl ring; and r is 2 to 6;

-   -   -   -   h) a group of the formula:

where R¹⁶ and R¹⁷ are each independently hydrogen; (C₁₋₈)alkyl;(C₁₋₆)alkylcarbonyl; di-(C₁₋₆)alkylaminocarbonyl; benzyl; benzoyl;pyridine; pyrimidine; phenyl; phenylaminocarbonyl; alkylsulfonyl; orphenylsulfonyl; where the benzyl, benzoyl, pyridine, pyrimidine, phenyl,phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups areoptionally mono- or independently di-substituted with R¹²; or R¹⁶ andR¹⁷ together form a (C₃₋₁₂)cycloalkyl ring; and s is 1 to 6;

-   -   -   -   i) a group of the formula:

where R¹⁸ and R¹⁹ are independently hydrogen; (C₁₋₈)alkyl;(C₁₋₆)alkylcarbonyl; di-(C₁₋₆)alkylaminocarbonyl; benzyl; benzothiazole;benzoyl; pyridine; pyrimidine; phenyl; phenylaminocarbonyl;alkylsulfonyl, or phenylsulfonyl; where the benzyl, benzoyl,benzothiazole, pyridine, pyrimidine, phenyl, phenylaminocarbonyl,alkylsulfonyl, and phenylsulfonyl groups are optionally mono- orindependently di-substituted with R¹²; or R¹⁸ and R¹⁹ together form a(C₃₋₁₂)cycloalkyl ring; each t is independently 0 to 6; and u is 0 to 3;

-   -   -   -   j) a group of the formula:

(phenyl-CH₂—C(CH₃)₂—),

where the phenyl group is optionally mono- or independentlyplurisubstituted with R¹²;

-   -   -   -   k) a group of the formula:

where R²⁹ is hydrogen; (C₁₋₈)alkyl; (C₁₋₆)alkylcarbonyl;di-(C₁₋₆)alkylaminocarbonyl; (C₃₋₈)cycloalkylcarbonyl; benzyl; benzoyl;(C₁₋₆)alkyloxycarbonyl; arlkyloxycarbonyl, pyridine; pyrimidine; phenyl;phenyl substituted thiazole ring; phenylaminocarbonyl; alkylsulfonyl; orphenylsulfonyl; where the benzyl, benzoyl, pyridine, pyrimidine, phenyl,phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups areoptionally mono- or independently di-substituted with R¹²; R_(x) ishydrogen; (C₁₋₈)alkyl; (C₃₋₁₂)cycloalkyl; benzyl; phenyl; where thebenzyl and phenyl, groups are optionally mono- or independentlydi-substituted on the ring with R¹²; R_(y) is absent or is halogen,(C₁₋₈)alkyl, (C₁₋₈)alkoxy, O-alkylcarboxylate, O-aralkylcarboxylate,N-alkylcarboxamido, N-aralkylcarboxamido; or phenyl; s is 1 to 6; t is 0to 6; and u is 0 to 3; or

-   -   -   -   l) a group of the formula:

where R²¹ is hydrogen; (C₁₋₈)alkyl; benzyl; or phenyl; in which thebenzyl and phenyl groups are optionally mono- or independentlydi-substituted on the ring with R¹²; each t is independently 0 to 6; andu is 0 to 3;

-   -   -   (bb) R^(i), R^(ii), R³, R⁴ and R⁵ are independently            hydrogen; alkyl; alkenyl; alkynyl; cycloalkyl;            cycloalkylalkyl; bicycloalkyl; tricycloalkyl;            alkylcycloalkyl; hydroxyalkyl; hydroxyalkylcycloalkyl;            hydroxycycloalkyl; hydroxybicycloalkyl;            hydroxytricycloalkyl; bicycloalkylalkyl; alkylbicycloalkyl;            alkylthioalkyl; arylalkylthioalkyl; cycloalkenyl; aryl,            aralkyl; heteroaryl; heteroarylalkyl; cycloheteroalkyl or            cycloheteroalkylalkyl; all optionally mono- or independently            plurisubstituted with halogen, alkyl, polyhaloalkyl, alkoxy,            haloalkoxy, polyhaloalkoxy, alkoxycarbonyl, alkenyl,            alkynyl, cycloalkyl, cycloalkylalkyl, polycycloalkyl,            heteroarylamino, arylamino, cycloheteroalkyl,            cycloheteroalkylalkyl, hydroxy, hydroxyalkyl, nitro, cyano,            amino, substituted amino, alkylamino, dialkylamino, thiol,            alkylthio, alkylcarbonyl, acyl, alkoxycarbonyl,            aminocarbonyl, alkynylamino-carbonyl, alkylaminocarbonyl,            alkenylaminocarbonyl, alkylcarbonyloxy, alkylcarbonylamino,            arylcarbonylamino, alkylsulfonylamino,            alkylaminocarbonyl-amino, alkoxycarbonylamino,            alkylsulfonyl, aminosulfinyl, aminosulfonyl, alkylsulfinyl,            sulfonamido or sulfonyl; or            -   R^(i) together with R³ or R⁴, or together with R³ or R⁴,                and the atoms to which they are attached form a 4 to 8                membered cyclic, polycyclic or heterocyclic ring system                containing 1 to 3 heteroatoms selected from N, O, S, SO                or SO₂; and includes single rings, fused bicyclic and                tricyclic rings, which are optionally mono- or                independently plurisubstituted with any of the groups                set forth in (aa); or            -   R⁴ and R⁵ together form —(CR²²R²³)_(m)— where m is 2 to                6, and R²² and R²³ are independently hydrogen; hydroxyl;                alkoxy; alkyl; alkenyl; alkynyl; cycloalkyl; halo;                amino; substituted amino; cycloalkylalkyl; cycloalkenyl;                aryl; arylalkyl; heteroaryl, heteroarylalkyl;                cycloheteroalkyl; cycloheteroalkylalkyl;                alkylcarbonylamino; arylcarbonylamino;                alkoxycarbonyl-amino; aryloxycarbonyl-amino;                alkoxycarbonyl; aryloxycarbonyl; or                alkylaminocarbonylamino; or            -   R⁴ and R⁵ together with the atoms to which they are                attached form a 5 to 7 membered ring containing a total                of 2 to 4 heteroatoms selected from N, O, S, SO, or SO₂;                or            -   R⁴ and R⁵ together with the atoms to which they are                attached form a 4 to 8 membered cycloheteroalkyl ring                wherein the cycloheteroalkyl ring optionally has an                aryl, heteroaryl or 3 to 7 membered cycloalkyl ring                fused thereto; or        -   (cc) R^(i) and R³ are hydrogen; and R^(ii) and R⁴ together            form a 4 to 8 membered cyclic, polycyclic or heterocyclic            ring system containing 1 to 3 heteroatoms selected from N,            O, S, SO and SO₂, and includes single rings, fused bicyclic            and tricyclic rings, which are optionally mono- or            independently plurisubstituted with any of the groups set            forth in (aa) or (bb) and            -   R⁵ is any of the groups in (aa) or (bb); and

if CR^(i)R^(ii) is absent, then R³, R⁴ and R⁵ are selected from (dd),(ee) or (ff):

-   -   (dd) R³ and R⁴ are hydrogen; and        -   R⁵ is            -   a) hydrogen, provided that R⁵ is not hydrogen when n is                1, X is CH₂, and Z is H;            -   b) (C₁₋₁₂)alkyl; (C₂₋₁₂)alkenyl; (C₂₋₁₂)alkynyl; (C₃₋₁₂)                cycloalkyl; or (C₃₋₁₂)cycloalkenyl; where the alkyl,                alkenyl, alkynyl, cycloalkyl and cycloalkenyl groups are                optionally mono- or independently plurisubstituted with                R⁶, and where the alkyl, alkenyl, alkynyl portions                include linear or branched chains and may include cyclic                portions;            -   R⁶ is (C₁₋₆)alkyl; (C₁₋₆)alkoxy; cycloalkyl; carboxy;                acetamido; cyano; nitro; halogen; hydroxy;                hydroxy(C₁₋₆)alkyl; hydroxymethyl; trifluoromethyl;                trifluoromethoxy; sulfamoyl; sulfonamido; carbamoyl;                aryl; heteroaryl; where the aryl and heteroaryl groups                are optionally mono- or independently plurisubstituted                with R⁷; amino, where the amino group is optionally                mono- or independently plurisubstituted with R⁸; —SOR⁸;                —SO₂R⁸; —COR⁸; —CO₂R⁸, —CONHR⁸; —CON(R⁸)₂; —OR⁸; or                —S—R⁸;            -   R⁷ is halogen; (C₁₋₁₀)alkyl; (C₁₋₁₀)alkoxy;                (C₁₋₁₀)alkylamino; (C₁₋₁₀)dialkylamino; benzyl;                benzyloxy; hydroxyl(C₁₋₆)alkyl; hydroxymethyl; nitro;                trifluoromethyl; trifluoromethoxy; trifluoromethylthio;                N-hydroxyimino; cyano; carboxy; acetamido; hydroxy;                sulfamoyl; sulfonamido; or carbamoyl;            -   R⁸ is (C₁₋₁₀)alkyl; (C₂₋₁₀)alkenyl; (C₂₋₁₀)alkynyl;                (C₃₋₁₀)cycloalkyl; (C₅₋₁₀)cycloalkenyl; benzyl;                phenethyl; aryl; or heteroaryl; where the alkyl,                alkenyl, alkynyl, cycloalkyl, cycloalkenyl groups are                optionally mono- or independently plurisubstituted with                aryl or heteroaryl where the aryl and heteroaryl groups                are optionally mono- or independently plurisubstituted                with R⁷; and where the aryl and heteroaryl groups are                optionally mono- or independently plurisubstituted with                R⁷;            -   c) aryl optionally fused to a (C₃₋₁₀)cycloalkyl; or                heteroaryl optionally fused to a (C₃₋₁₀)cycloalkyl;                where the aryl and heteroaryl groups are optionally                mono- or independently plurisubstituted with R⁷;            -   d) indanyl; 1,2,3,4-tetrahydronaphthyl;                (CH₂)_(j)adamantyl in which j is 0-3; or a [2.2.1] or                [3.1.1] bicyclic carbocyclic moiety, including                (4-pentylbicyclo[2.2.2]oct-1-yl)amine; where the                indanyl, 1,2,3,4-tetrahydronaphthyl, (CH₂)_(j)                adamantyl, and [2.2.1] or [3.1.1] bicyclic carbocyclic                moieties are optionally mono- or independently                plurisubstituted with hydroxy, (C₁₋₈)alkyl,                (C₁₋₈)alkoxy, (C₁₋₈)alkanoyloxy, or R⁹R¹⁰N—CO—O—, where                R⁹ and R¹⁰ are independently (C₁₋₈)alkyl, or phenyl,                where the alkyl and phenyl groups are optionally mono-                or independently plurisubstituted with (C₁₋₈)alkyl,                (C₁₋₈)alkoxy, halogen, or trifluoromethyl, or R⁹ and R¹⁰                together are (C₃₋₆)alkylene;            -   e) R¹¹(CH₂)_(p)— where R¹¹ is 2-oxopyrrolidinyl;                (C₁₋₆)alkoxy; phenyl; phenoxy; (C₁₋₈)cycloalkyl; [3.3.3]                bicyclic carbocyclic moiety; pyridinyl; naphthyl;                cyclohexenyl; or adamantyl; where the 2-oxopyrrolidinyl,                (C₁₋₆)alkoxy, phenyl, pyridinyl, and naphthyl groups are                optionally mono- or independently di- or independently                trisubstituted with R¹²; where the phenoxy group is                optionally mono- or independently disubstituted with                (C₁₋₄)alkyl, (C₁₋₄)alkoxy, or halogen; and where the                [3.3.3] bicyclic carbocyclic moiety is optionally                mono-or independently plurisubstituted with (C₁₋₈)alkyl;                and p is 0 to 3;            -   R¹² is halogen; trifluoromethyl; cyano; nitro;                (C₁₋₆)alkyl; (C₁₋₆)alkoxy; cycloalkyl; carboxy;                acetamido; hydroxy; hydroxy(C₁₋₆)alkyl; hydroxymethyl;                trifluoromethoxy; sulfamoyl; carbamoyl; sulfonamido;                alkylsufonyl; phenylsulfonyl; aryl; heteroaryl; where                the aryl and heteroaryl groups are optionally mono- or                independently plurisubstituted with R⁷;            -   (R¹³)₂CH(CH₂)_(q)—, where R¹³ is phenyl; in which the                phenyl groups are independently optionally mono- or                independently disubstituted with R¹²; and q is 0 to 3;            -   g) a group of the formula:

where R¹⁴ and R¹⁵ are independently hydrogen; (C₁₋₈)alkyl;(C₁₋₆)alkylcarbonyl; (C₃₋₁₂)cycloalkyl ring; (C₃₋₁₂)cycloalkenyl ring;benzyl; benzoyl; pyridine; pyrimidine; phenyl; phenylamino-carbonyl;alkylsulfonyl; or phenylsulfonyl; where the cycloalkyl ring isoptionally substituted with hydroxy(C₁₋₆)alkyl, and where the benzyl,benzoyl, pyridine, pyrimidine, phenyl, phenylaminocarbonyl,alkylsulfonyl, and phenylsulfonyl groups are optionally mono- orindependently di-substituted with R¹²; or R¹⁴ and R¹⁵ together form a(C₃₋₁₂)cycloalkyl ring; and r is 2 to 6;

-   -   -   -   h) a group of the formula:

where R¹⁶ and R¹⁷ are each independently hydrogen; (C₁₋₈)alkyl;(C₁₋₆)alkylcarbonyl; di-(C₁₋₆)alkylaminocarbonyl; benzyl; benzoyl;pyridine; pyrimidine; phenyl; phenylaminocarbonyl; alkylsulfonyl; orphenylsulfonyl; where the benzyl, benzoyl, pyridine, pyrimidine, phenyl,phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups areoptionally mono- or independently di-substituted with R¹²; or R¹⁶ andR¹⁷ together form a (C₃₋₁₂)cycloalkyl ring; and s is 1 to 6;

-   -   -   -   i) a group of the formula:

where R¹⁸ and R¹⁹ are independently hydrogen; (C₁₋₈)alkyl;(C₁₋₆)alkylcarbonyl; di-(C₁₋₆)alkylaminocarbonyl; benzyl; benzothiazole;benzoyl; pyridine; pyrimidine; phenyl; phenylaminocarbonyl;alkylsulfonyl; or phenylsulfonyl; where the benzyl, benzoyl,benzothiazole, pyridine, pyrimidine, phenyl, phenylaminocarbonyl,alkylsulfonyl, and phenylsulfonyl groups are optionally mono- orindependently di-substituted with R¹²; or R¹⁸ and R¹⁹ together form a(C₃₋₁₂)cycloalkyl ring; each t is independently 0 to 6; and u is 0 to 3;

-   -   -   -   j) a group of the formula:

(phenyl-CH₂—C(CH₃)₂—),

where the phenyl group is optionally mono- or independentlyplurisubstituted with R¹²;

-   -   -   -   k) a group of the formula:

where R²⁰ is hydrogen; (C₁₋₈)alkyl; (C₁₋₆)alkylcarbonyl;di-(C₁₋₆)alkylaminocarbonyl; (C₃₋₈)cycloalkylcarbonyl; benzyl; benzoyl;(C₁₋₆)alkyloxycarbonyl; arlkyloxycarbonyl, pyridine; pyrimidine; phenyl;phenyl substituted thiazole ring; phenylaminocarbonyl; alkylsulfonyl; orphenylsulfonyl; where the benzyl, benzoyl, pyridine, pyrimidine, phenyl,phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups areoptionally mono- or independently di-substituted with R¹²; R_(x) ishydrogen; (C₁₋₈)alkyl; (C₃₋₁₂)cycloalkyl; benzyl; phenyl; where thebenzyl and phenyl, groups are optionally mono- or independentlydi-substituted on the ring with R¹²; R_(y) is absent or is halogen,(C₁₋₈)alkyl, (C₁₋₈)alkoxy, O-alkylcarboxylate, O-aralkylcarboxylate,N-alkylcarboxamido, N-aralkylcarboxamido; or phenyl; s is 1 to 6;t is 0to 6; and u is 0 to 3; or

-   -   -   -   l) a group of the formula:

where R²¹ is hydrogen; (C₁₋₈)alkyl; benzyl; or phenyl; in which thebenzyl and phenyl groups are optionally mono- or independentlydi-substituted on the ring with R¹²; each t is independently 0 to 6; andu is 0 to 3; or

-   -   (ee) R³, R⁴ and R⁵ are independently hydrogen; alkyl; alkenyl;        alkynyl; cycloalkyl; cycloalkylalkyl; bicycloalkyl;        tricycloalkyl; alkylcycloalkyl; hydroxyalkyl;        hydroxyalkylcycloalkyl; hydroxycycloalkyl; hydroxybicycloalkyl;        hydroxytricycloalkyl; bicycloalkylalkyl; alkylbicycloalkyl;        alkylthioalkyl; arylalkylthioalkyl; cycloalkenyl; aryl, aralkyl;        heteroaryl; heteroarylalkyl; cycloheteroalkyl or        cycloheteroalkylalkyl; all optionally mono- or independently        plurisubstituted with halogen, alkyl, polyhaloalkyl, alkoxy,        haloalkoxy, polyhaloalkoxy, alkoxycarbonyl, alkenyl, alkynyl,        cycloalkyl, cycloalkylalkyl, polycycloalkyl, heteroarylamino,        arylamino, cycloheteroalkyl, cycloheteroalkylalkyl, hydroxy,        hydroxyalkyl, nitro, cyano, amino, substituted amino,        alkylamino, dialkylamino, thiol, alkylthio, alkylcarbonyl, acyl,        alkoxycarbonyl, aminocarbonyl, alkynylaminocarbonyl,        alkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyloxy,        alkylcarbonylamino, arylcarbonylamino, alkylsulfonylamino,        alkylaminocarbonyl-amino, alkoxycarbonylamino, alkylsulfonyl,        aminosulfinyl, aminosulfonyl, alkylsulfinyl, sulfonamido or        sulfonyl, provided that when n is 1, X is CH₂, the ring        containing X is saturated, and Z, R³ and R⁵ are H, R⁴ is not a        side chain of a naturally occurring α-amino acid, and provided        that when n is 1, X is CH₂, the ring containing X is saturated,        and Z and R⁵ are H, R³ and R⁴ are not both methyl; or        -   -   R⁴ and R⁵ together form —(CR²²R²³)_(m)— where m is 2 to                6, and R²² and

R²³ are independently hydrogen; hydroxyl; alkoxy; alkyl; alkenyl;alkynyl; cycloalkyl; halo; amino; substituted amino; cycloalkylalkyl;cycloalkenyl; aryl; arylalkyl; heteroaryl, heteroarylalkyl;cycloheteroalkyl; cycloheteroalkylalkyl; alkylcarbonylamino;arylcarbonylamino; alkoxycarbonyl-amino; aryloxycarbonyl-amino;alkoxycarbonyl; aryloxycarbonyl; or alkylaminocarbonylamino; providedthat when n is 1, X is CH₂, the ring containing X is saturated, Z and R³are H, R⁴ and R⁵ together are not —(CH₂)₂— or —(CH₂)₃—; or

-   -   -   -   R⁴ and R⁵ together with the atoms to which they are                attached form a 5 to 7 membered ring containing a total                of 2 to 4 heteroatoms selected from N, O, S, SO, or SO₂;                or            -   R⁴ and R⁵ together with the atoms to which they are                attached form a 4 to 8 membered cycloheteroalkyl ring                wherein the cycloheteroalkyl ring optionally has an                aryl, heteroaryl or 3 to 7 membered cycloalkyl ring                fused thereto; or

    -   (ff) R³ is hydrogen; and R⁴ and R⁵ together with the atoms to        which they are attached form a 4 to 8 member mono- or polycyclic        heterocyclic ring system containing 1 to 3 heteroatoms selected        from N, O, S, SO and SO₂, wherein the heterocyclic ring system        is optionally mono- or independently plurisubstituted with any        of the groups set forth in (dd) or (ee); provided that when n is        1, X is CH₂, the ring containing X is saturated, and Z and R³        are H, R⁴ and R⁵ together are not —(CH₂)₂— or —(CH₂)₃—; and

wherein the bond containing the wavy line signifies the point ofattachment.

In some embodiments of compounds of formula I, R¹ and R² independentlyor together are the boronic acid protecting group formed from(+)-pinanediol; pinacol; 1,2-dicyclohexyl-ethanediol; 1,2-ethanediol;2,2-diethanolamine; 1,3 -propanediol; 2,3-butanediol, diisopropyltartrate; 1,4-butanediol; diisopropylethanediol; (S,S,)-5,6-decanediol;1,1,2-triphenyl-1,2-ethanediol;(2R,3R)-1,4-dimethyoxy-1,1,4,4-tetraphenyl-2,3-butanediol; methanol;ethanol; isopropanol; catechol; or 1-butanol. Thus, it will beunderstood by those of skill in the art that R¹ and R² represent asingle protecting group attached to both boronic ester oxygens whendiols such as (+)-pinanediol and pinacol are used, whereas R¹ and R²represent separate moieties on the boronic ester oxygens such as methylor ethyl when the esters are formed from methanol and ethanol,respectively. In other embodiments of compounds of formula I, R¹ and R²independently or together are a group capable of being hydrolyzed to ahydroxyl group in an aqueous solution at physiological pH or inbiological fluids and are formed from 1,2-dicyclohexylethanediol;1,2-ethanediol; 1,3-propanediol; 2,3-butanediol, 1,4-butanediol;diisopropylethanediol; methanol; ethanol; isopropanol; or 1-butanol. Forexample, when R¹ and R² are each formed from methanol, the resulting R¹and R² groups are methyl. When 2,3-butanediol is used, the resulting R¹and R² groups are a single group and the resulting boronic ester has thefollowing structure:

Compounds of formula I include those wherein if CR^(i)R^(ii) is absent,then R³, R⁴ and R⁵ are selected from (dd), (ee) or (ff):

-   -   (dd) R³ and R⁴ are hydrogen; and        -   R⁵ is            -   a) (C₁₋₁₂)alkyl; (C₂₋₁₂)alkenyl; (C₂₋₁₂)alkynyl; (C₃₋₁₂)                cycloalkyl; or (C₃₋₁₂)cycloalkenyl; where the alkyl,                alkenyl, alkynyl, cycloalkyl and cycloalkenyl groups are                optionally mono- or independently plurisubstituted with                R⁶, and where the alkyl, alkenyl, alkynyl portions                include linear or branched chains and may include cyclic                portions;            -   R⁶ is (C₁₋₆)alkyl; (C₁₋₆)alkoxy; cycloalkyl; carboxy;                acetamido; cyano; nitro; halogen; hydroxy;                hydroxy(C₁₋₆)alkyl; hydroxymethyl; trifluoromethyl;                trifluoromethoxy; sulfamoyl; sulfonamido; carbamoyl;                aryl; heteroaryl; where the aryl and heteroaryl groups                are optionally mono- or independently plurisubstituted                with R⁷; amino, where the amino group is optionally                mono- or independently plurisubstituted with R⁸; —SOR⁸;                —SO₂R⁸; —COR^(S); —CO₂R⁸, —CONHR⁸; —CON(R⁸)₂; —OR⁸; or                —S—R⁸;            -   R⁷ is halogen; (C₁₋₁₀)alkyl; (C₁₋₁₀)alkoxy;                (C₁₋₁₀)alkylamino; (C₁₋₁₀)dialkylamino; benzyl;                benzyloxy; hydroxyl(C₁₋₆)alkyl; hydroxymethyl; nitro;                trifluoromethyl; trifluoromethoxy; trifluoromethylthio;                N-hydroxyimino; cyano; carboxy; acetamido; hydroxy;                sulfamoyl; sulfonamido; or carbamoyl;            -   R⁸ is (C₁₋₁₀)alkyl; (C₂₋₁₀)alkenyl; (C₂₋₁₀)alkynyl;                (C₃₋₁₀)cycloalkyl; (C₅₋₁₀)cycloalkenyl; benzyl;                phenethyl; aryl; or heteroaryl; where the alkyl,                alkenyl, alkynyl, cycloalkyl, cycloalkenyl groups are                optionally mono- or independently plurisubstituted with                aryl or heteroaryl where the aryl and heteroaryl groups                are optionally mono- or independently plurisubstituted                with R⁷; and where the aryl and heteroaryl groups are                optionally mono- or independently plurisubstituted with                R⁷;            -   b) aryl optionally fused to a (C₃₋₁₀)cycloalkyl; or                heteroaryl optionally fused to a (C₃₋₁₀)cycloalkyl;                where the aryl and heteroaryl groups are optionally                mono- or independently plurisubstituted with R⁷;            -   c) indanyl; 1,2,3,4-tetrahydronaphthyl;                (CH₂)_(j)adamantyl in which j is 0-3; or a [2.2.1] or                [3.1.1] bicyclic carbocyclic moiety, including                (4-pentylbicyclo[2.2.2]oct-1-yl)amine; where the                indanyl, 1,2,3,4-tetrahydronaphthyl, (CH₂)_(j)                adamantyl, and [2.2.1] or [3.1.1] bicyclic carbocyclic                moieties are optionally mono- or independently                plurisubstituted with hydroxy, (C₁₋₈)alkyl,                (C₁₋₈)alkoxy, (C₁₋₈)alkanoyloxy, or R⁹R¹⁰N—CO—O—, where                R⁹ and R¹⁰ are independently (C₁₋₈)alkyl, or phenyl,                where the alkyl and phenyl groups are optionally mono-                or independently plurisubstituted with (C₁₋₈)alkyl,                (C₁₋₈)alkoxy, halogen, or trifluoromethyl, or R⁹ and R¹⁰                together are (C₃₋₆)alkylene;            -   d) R¹¹(CH₂)_(p)— where R¹¹ is 2-oxopyrrolidinyl;                (C₁₋₆)alkoxy; phenyl; phenoxy; (C₁₋₈)cycloalkyl; [3.3.3]                bicyclic carbocyclic moiety; pyridinyl; naphthyl;                cyclohexenyl; or adamantyl; where the 2-oxopyrrolidinyl,                (C₁₋₆)alkoxy, phenyl, pyridinyl, and naphthyl groups are                optionally mono- or independently di- or independently                trisubstituted with R¹²; where the phenoxy group is                optionally mono- or independently disubstituted with                (C₁₋₄)alkyl, (C₁₋₄)alkoxy, or halogen; and where the                [3.3.3] bicyclic carbocyclic moiety is optionally                mono-or independently plurisubstituted with (C₁₋₈)alkyl;                and p is 0 to 3;            -   R¹² is halogen; trifluoromethyl; cyano; nitro;                (C₁₋₆)alkyl; (C₁₋₆)alkoxy; cycloalkyl; carboxy;                acetamido; hydroxy; hydroxy(C₁₋₆)alkyl; hydroxymethyl;                trifluoromethoxy; sulfamoyl; carbamoyl; sulfonamido;                alkylsufonyl; phenylsulfonyl; aryl; heteroaryl; where                the aryl and heteroaryl groups are optionally mono- or                independently plurisubstituted with R⁷;            -   e) (R¹³)₂CH(CH₂)_(q)—, where R¹³ is phenyl; in which the                phenyl groups are independently optionally mono- or                independently disubstituted with R¹²; and q is 0 to 3;            -   f) a group of the formula:

where R¹⁴ and R¹⁵ are independently hydrogen; (C₁₋₈)alkyl;(C₁₋₆)alkylcarbonyl; (C₃₋₁₂)cycloalkyl ring; (C₃₋₁₂)cycloalkenyl ring;benzyl; benzoyl; pyridine; pyrimidine; phenyl; phenylamino-carbonyl;alkylsulfonyl; or phenylsulfonyl; where the cycloalkyl ring isoptionally substituted with hydroxy(C₁₋₆)alkyl, and where the benzyl,benzoyl, pyridine, pyrimidine, phenyl, phenylaminocarbonyl,alkylsulfonyl, and phenylsulfonyl groups are optionally mono- orindependently di-substituted with R¹²; or R¹⁴ and R¹⁵ together form a(C₃₋₁₂)cycloalkyl ring; and r is 2 to 6;

-   -   -   -   g) a group of the formula:

where R¹⁶ and R¹⁷ are each independently hydrogen; (C₁₋₈)alkyl;(C₁₋₆)alkylcarbonyl; di-(C₁₋₆)alkylaminocarbonyl; benzyl; benzoyl;pyridine; pyrimidine; phenyl; phenylaminocarbonyl; alkylsulfonyl; orphenylsulfonyl; where the benzyl, benzoyl, pyridine, pyrimidine, phenyl,phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups areoptionally mono- or independently di-substituted with R¹²; or R¹⁶ andR¹⁷ together form a (C₃₋₁₂)cycloalkyl ring; and s is 1 to 6;

-   -   -   -   h) a group of the formula:

where R¹⁸ and R¹⁹ are independently hydrogen; (C₁₋₈)alkyl;(C₁₋₆)alkylcarbonyl; di-(C₁₋₆)alkylaminocarbonyl; benzyl; benzothiazole;benzoyl; pyridine; pyrimidine; phenyl; phenylaminocarbonyl;alkylsulfonyl; or phenylsulfonyl; where the benzyl, benzoyl,benzothiazole, pyridine, pyrimidine, phenyl, phenylaminocarbonyl,alkylsulfonyl, and phenylsulfonyl groups are optionally mono- orindependently di-substituted with R¹²; or R¹⁸ and R¹⁹ together form a(C₃₋₁₂)cycloalkyl ring; each t is independently 0 to 6; and u is 0 to 3;

-   -   -   -   i) a group of the formula:

(phenyl-CH₂—C(CH₃)₂—),

where the phenyl group is optionally mono- or independentlyplurisubstituted with R¹²;

-   -   -   -   j) a group of the formula:

where R²⁰ is hydrogen; (C₁₋₈)alkyl; (C₁₋₆)alkylcarbonyl;di-(C₁₋₆)alkylaminocarbonyl; (C₃₋₈)cycloalkylcarbonyl; benzyl; benzoyl;(C₁₋₆)alkyloxycarbonyl; arlkyloxycarbonyl, pyridine; pyrimidine; phenyl;phenyl substituted thiazole ring; phenylaminocarbonyl; alkylsulfonyl; orphenylsulfonyl; where the benzyl, benzoyl, pyridine, pyrimidine, phenyl,phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups areoptionally mono- or independently di-substituted with R¹²; R_(x) ishydrogen; (C₁₋₈)alkyl; (C₃₋₁₂)cycloalkyl; benzyl; phenyl; where thebenzyl and phenyl, groups are optionally mono- or independentlydi-substituted on the ring with R¹²; R_(y) is absent or is halogen,(C₁₋₈)alkyl, (C₁₋₈)alkoxy, O-alkylcarboxylate, O-aralkylcarboxylate,N-alkylcarboxamido, N-aralkylcarboxamido; or phenyl; s is 1 to 6;t is 0to 6; and u is 0 to 3; or

-   -   -   -   k) a group of the formula:

where R²¹ is hydrogen; (C₁₋₈)alkyl; benzyl; or phenyl; in which thebenzyl and phenyl groups are optionally mono- or independentlydi-substituted on the ring with R¹²; each t is independently 0 to 6; andu is 0 to 3; or

-   -   (ee) R³ and R⁴ are independently hydrogen, alkyl; alkenyl;        alkynyl; cycloalkyl; cycloalkylalkyl; bicycloalkyl;        tricycloalkyl; alkylcycloalkyl; hydroxyalkyl;        hydroxyalkylcycloalkyl; hydroxycycloalkyl; hydroxybicycloalkyl;        hydroxytricycloalkyl; bicycloalkylalkyl; alkylbicycloalkyl;        alkylthioalkyl; arylalkylthioalkyl; cycloalkenyl; aryl, aralkyl;        heteroaryl; heteroarylalkyl; cycloheteroalkyl or        cycloheteroalkylalkyl; all optionally mono- or independently        plurisubstituted with halogen, alkyl, polyhaloalkyl, alkoxy,        haloalkoxy, polyhaloalkoxy, alkoxycarbonyl, alkenyl, alkynyl,        cycloalkyl, cycloalkylalkyl, polycycloalkyl, heteroarylamino,        arylamino, cycloheteroalkyl, cycloheteroalkylalkyl, hydroxy,        hydroxyalkyl, nitro, cyano, amino, substituted amino,        alkylamino, dialkylamino, thiol, alkylthio, alkylcarbonyl, acyl,        alkoxycarbonyl, aminocarbonyl, alkynylaminocarbonyl,        alkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyloxy,        alkylcarbonylamino, arylcarbonylamino, alkylsulfonylamino,        alkylaminocarbonyl-amino, alkoxycarbonylamino, alkylsulfonyl,        aminosulfinyl, aminosulfonyl, alkylsulfinyl, sulfonamido or        sulfonyl;        -   -   R⁵ is alkyl; alkenyl; alkynyl; cycloalkyl;                cycloalkylalkyl; bicycloalkyl; tricycloalkyl;                alkylcycloalkyl; hydroxyalkyl; hydroxyalkylcycloalkyl;                hydroxycycloalkyl; hydroxybicycloalkyl;                hydroxytricycloalkyl; bicycloalkylalkyl;                alkylbicycloalkyl; alkylthioalkyl; arylalkylthioalkyl;                cycloalkenyl; aryl, aralkyl; heteroaryl;                heteroarylalkyl; cycloheteroalkyl or                cycloheteroalkylalkyl; all optionally mono- or                independently plurisubstituted with halogen, alkyl,                polyhaloalkyl, alkoxy, haloalkoxy, polyhaloalkoxy,                alkoxycarbonyl, alkenyl, alkynyl, cycloalkyl,                cycloalkylalkyl, polycycloalkyl, heteroarylamino,                arylamino, cycloheteroalkyl, cycloheteroalkylalkyl,                hydroxy, hydroxyalkyl, nitro, cyano, amino, substituted                amino, alkylamino, dialkylamino, thiol, alkylthio,                alkylcarbonyl, acyl, alkoxycarbonyl, aminocarbonyl,                alkynylaminocarbonyl, alkylaminocarbonyl,                alkenylaminocarbonyl, alkylcarbonyloxy,                alkylcarbonylamino, arylcarbonylamino,                alkylsulfonylamino, alkylaminocarbonyl-amino,                alkoxycarbonylamino, alkylsulfonyl, aminosulfinyl,                aminosulfonyl, alkylsulfinyl, sulfonamido or sulfonyl;                or            -   R⁴ and R⁵ together form —(CR²²R²³)_(m)— wherein m is 2                to 6, and R²² and R²³ are independently hydrogen;                hydroxyl; alkoxy; alkyl; alkenyl; alkynyl; cycloalkyl;                halo; amino; substituted amino; cycloalkylalkyl;                cycloalkenyl; aryl; arylalkyl; heteroaryl,                heteroarylalkyl; cycloheteroalkyl;                cycloheteroalkylalkyl; alkylcarbonylamino;                arylcarbonylamino; alkoxycarbonyl-amino;                aryloxycarbonyl-amino; alkoxycarbonyl; aryloxycarbonyl;                or alkylaminocarbonylamino; provided that when n is 1, X                is CH₂, and Z and R³ are H, R⁴ and R⁵ together are not                —(CH₂)₂— or —(CH₂)₃—; or            -   R⁴ and R⁵ together with the atoms to which they are                attached form a 5 to 7 membered ring containing a total                of 2 to 4 heteroatoms selected from N, O, S, SO, or SO₂;                or            -   R⁴ and R⁵ together with the atoms to which they are                attached form a 4 to 8 membered cycloheteroalkyl ring                wherein the cycloheteroalkyl ring optionally has an                aryl, heteroaryl or 3 to 7 membered cycloalkyl ring                fused thereto; or            -   (ff) R³ is hydrogen; and R⁴ and R⁵ together with the                atoms to which they are attached form a 4 to 8 member                mono- or polycyclic heterocyclic ring system containing                1 to 3 heteroatoms selected from N, O, S, SO and SO₂,                wherein the heterocyclic ring system is optionally mono-                or independently plurisubstituted with any of the groups                set forth in (dd) or (ee); provided that when n is 1, X                is CH₂, the ring containing X is saturated, and Z and R³                are H, R⁴ and R⁵ together are not —(CH₂)₂— or —(CH₂)₃—.

Compounds of formula I also include those wherein X is CH₂; the ringcontaining X is saturated; CR^(i)R^(ii) is absent, R¹, R², R³ and R⁴ arehydrogen; and R⁵ is (C₁₋₁₂)alkyl; (C₂₋₁₂)alkenyl; (C₂₋₁₂)alkynyl;(C₃₋₁₂)cycloalkyl; or (C₃₋₁₂)cycloalkenyl; where the alkyl, alkenyl,alkynyl, cycloalkyl and cycloalkenyl groups are optionally mono- orindependently plurisubstituted with R⁶, and where the alkyl, alkenyl,alkynyl portions include linear or branched chains and may includecyclic portions. In some such embodiments, R⁵ is a (C₁₋₁₂)alkyl or(C₃₋₁₂)cycloalkyl, including, but not limited to, methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexylmethyl,1-cyclohexylethyl, or adamantyl.

In some embodiments of compounds of formula I, X is CH₂; the ringcontaining X is saturated; CR^(i)R^(ii)is absent, R¹, R², R³ and R⁴ arehydrogen; and R⁵ is indanyl; 1,2,3,4-tetrahydronaphthyl; (CH₂);adamantyl in which j is 0-3; or a [2.2.1] or [3.1.1] bicycliccarbocyclic moiety, including (4-pentylbicyclo[2.2.2]-oct-1-yl)amine;where the indanyl, 1,2,3,4-tetrahydronaphthyl, (CH₂) adamantyl, and[2.2.1] or [3.1.1] bicyclic carbocyclic moieties are optionally mono- orindependently plurisubstituted with hydroxy, (C₁₋₈)alkyl, (C₁₋₈)alkoxy,(C₁₋₈)alkanoyloxy, or R⁹R¹⁰N—CO—O—, where R⁹ and R¹⁰ are independently(C₁₋₈)alkyl, or phenyl, where the alkyl and phenyl groups are optionallymono- or independently plurisubstituted with (C₁₋₈)alkyl, (C₁₋₈)alkoxy,halogen, or trifluoromethyl, or R⁹ and R¹⁰ together are (C₃₋₆)alkylene.

In other embodiments of compounds of formula I, X is CH₂; the ringcontaining X is saturated; CR^(i)R^(ii) is absent, R¹, R², R³ and R⁴ arehydrogen; and R⁵ is R¹¹(CH₂)_(p)— where R¹¹ is 2-oxopyrrolidinyl;(C₁₋₆)alkoxy; phenyl; phenoxy; (C₁₋₈)cycloalkyl; [3.3.3] bicycliccarbocyclic moiety; pyridinyl; naphthyl; cyclohexenyl; or adamantyl;where the 2-oxopyrrolidinyl, (C₁₋₆)alkoxy, phenyl, pyridinyl, andnaphthyl groups are optionally mono- or independently di- orindependently trisubstituted with R¹²; where the phenoxy group isoptionally mono- or independently disubstituted with (C₁₋₄)alkyl,(C₁₋₄)alkoxy, or halogen; and where the [3.3.3] bicyclic carbocyclicmoiety is optionally mono-or independently plurisubstituted with(C₁₋₈)alkyl; p is 0 to 3; and R¹² is halogen; trifluoromethyl; cyano;nitro; (C₁₋₆)alkyl; (C₁₋₆)alkoxy; cycloalkyl; carboxy; acetamido;hydroxy; hydroxy(C₁₋₆)alkyl; hydroxymethyl; trifluoromethoxy; sulfamoyl;carbamoyl; sulfonamido; alkylsufonyl; phenylsulfonyl; aryl; heteroaryl;where the aryl and heteroaryl groups are optionally mono- orindependently plurisubstituted with R⁷.

In certain embodiments of compounds of formula I, X is CH₂; the ringcontaining X is saturated; CR^(i)R^(ii) is absent; R¹, R², R³ and R⁴ arehydrogen; and R⁵ is (R¹³)₂CH(CH₂)_(q)—, where R¹³ is phenyl; in whichthe phenyl groups are independently optionally mono- or independentlydisubstituted with R¹²; and q is 0 to 3.

In some embodiments of compounds of formula I, X is CH₂; the ringcontaining X is saturated; CR^(i)R^(ii) is absent, R¹, R², R³ and R⁴ arehydrogen; and R⁵ is a group of the formula:

where R¹⁴ and R¹⁵ are independently hydrogen; (C₁₋₈)alkyl;(C₁₋₆)alkylcarbonyl; (C₃₋₁₂)cycloalkyl ring; (C₃₋₁₂)cycloalkenyl ring;benzyl; benzoyl; pyridine; pyrimidine; phenyl; phenylamino-carbonyl;alkylsulfonyl; or phenylsulfonyl; where the cycloalkyl ring isoptionally substituted with hydroxy(C₁₋₆)alkyl, and where the benzyl,benzoyl, pyridine, pyrimidine, phenyl, phenylaminocarbonyl,alkylsulfonyl, and phenylsulfonyl groups are optionally mono- orindependently di-substituted with R¹²; or R¹⁴ and R¹⁵ together form a(C₃₋₁₂)cycloalkyl ring; and r is 2 to 6.

Compounds of formula I include those wherein X is CH₂; the ringcontaining X is saturated; CR^(i)R^(ii) is absent, R¹, R², R³ and R⁴ arehydrogen; and R⁵ is a group of the formula:

where R¹⁶ and R¹⁷ are each independently hydrogen; (C₁₋₈)alkyl;(C₁₋₆)alkylcarbonyl; di-(C₁₋₆)alkylaminocarbonyl; benzyl; benzoyl;pyridine; pyrimidine; phenyl; phenylaminocarbonyl; alkylsulfonyl; orphenylsulfonyl; where the benzyl, benzoyl, pyridine, pyrimidine, phenyl,phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups areoptionally mono- or independently di-substituted with R¹²; or R¹⁶ andR¹⁷ together form a (C₃₋₁₂)cycloalkyl ring; and s is 1 to 6.

Compounds of formula I wherein X is CH₂; the ring containing X issaturated; CR^(i)R^(ii) is absent, R¹, R², R³ and R⁴ are hydrogen; andR⁵ is a group of the formula:

where R¹⁸ and R¹⁹ are independently hydrogen; (C₁₋₈)alkyl;(C₁₋₆)alkylcarbonyl; di-(C₁₋₆)alkylaminocarbonyl; benzyl; benzothiazole;benzoyl; pyridine; pyrimidine; phenyl; phenylaminocarbonyl;alkylsulfonyl; or phenylsulfonyl; where the benzyl, benzoyl,benzothiazole, pyridine, pyrimidine, phenyl, phenylaminocarbonyl,alkylsulfonyl, and phenylsulfonyl groups are optionally mono- orindependently di-substituted with R¹²; or R¹⁸ and R¹⁹ together form a(C₃₋₁₂)cycloalkyl ring; each t is independently 0 to 6; and u is 0 to 3.In some such embodiments, R⁵ has formula:

In some embodiments of compounds of formula I, X is CH₂; the ringcontaining X is saturated; CR^(i)R^(ii) is absent, R¹, R², R³ and R⁴ arehydrogen; and R⁵ is a group of the formula:

(phenyl-CH₂—C(CH₃)₂—)

where the phenyl group is optionally mono- or independentlyplurisubstituted with R¹².

Compounds of Formula I include those having the following structure,Formula IA:

In some such embodiments, R⁵ is alkyl; alkenyl; alkynyl; cycloalkyl;cycloalkylalkyl; bicycloalkyl; tricycloalkyl; alkylcycloalkyl;hydroxyalkyl; hydroxyalkylcycloalkyl; hydroxycycloalkyl;hydroxybicycloalkyl; hydroxytricycloalkyl; bicycloalkylalkyl;alkylbicycloalkyl; alkylthioalkyl; arylalkylthioalkyl; cycloalkenyl;aryl, aralkyl; heteroaryl; heteroarylalkyl; cycloheteroalkyl orcycloheteroalkylalkyl; all optionally mono- or independentlyplurisubstituted with halogen, alkyl, polyhaloalkyl, alkoxy, haloalkoxy,polyhaloalkoxy, alkoxycarbonyl, alkenyl, alkynyl, cycloalkyl,cycloalkylalkyl, polycycloalkyl, heteroarylamino, arylamino,cycloheteroalkyl, cycloheteroalkylalkyl, hydroxy, hydroxyalkyl, nitro,cyano, amino, substituted amino, alkylamino, dialkylamino, thiol,alkylthio, alkylcarbonyl, acyl, alkoxycarbonyl, aminocarbonyl,alkynylaminocarbonyl, alkylaminocarbonyl, alkenylaminocarbonyl,alkylcarbonyloxy, alkylcarbonylamino, arylcarbonylamino,alkylsulfonylamino, alkylaminocarbonyl-amino, alkoxycarbonylamino,alkylsulfonyl, aminosulfinyl, aminosulfonyl, alkylsulfinyl, sulfonamidoor sulfonyl. In other such embodiments, R⁵ is alkyl; alkenyl;cycloalkyl; cycloalkylalkyl; hydroxyalkyl; cycloalkenyl; aryl, aralkyl;heteroaryl; heteroarylalkyl; cycloheteroalkyl or cycloheteroalkylalkyl;all optionally mono- or independently plurisubstituted as describedabove (in, e.g., (cc)). In still other such embodiments, R⁵ is alkyl,cycloalkyl or cycloheteroalkyl, optionally mono- or independentlyplurisubstituted as described above. In some embodiments of compounds ofFormula IA, R³ and R⁴ are both hydrogen. In other embodiments, n is 1.In some embodiments of compounds of Formula IA where n is 1 and R¹, R²,R³, and R⁴ are hydrogen, R⁵ is not methyl.

Compounds of formula I include those wherein X is CH₂; the ringcontaining X is saturated; CR^(i)R^(ii) is absent, R¹, R², R³ and R⁴ arehydrogen; and R⁵ is a group of the formula:

where R²⁰ is hydrogen; (C₁₋₈)alkyl; (C₁₋₆)alkylcarbonyl;di-(C₁₋₆)alkylaminocarbonyl; (C₃₋₈)cycloalkylcarbonyl; benzyl; benzoyl;(C₁₋₆)alkyloxycarbonyl; arlkyloxycarbonyl, pyridine; pyrimidine; phenyl;phenyl substituted thiazole ring; phenylaminocarbonyl; alkylsulfonyl; orphenylsulfonyl; where the benzyl, benzoyl, pyridine, pyrimidine, phenyl,phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups areoptionally mono- or independently di-substituted with R¹²; R_(x) ishydrogen; (C₁₋₈)alkyl; (C₃₋₁₂)cycloalkyl; benzyl; phenyl; where thebenzyl and phenyl, groups are optionally mono- or independentlydi-substituted on the ring with R¹²; R_(y) is absent or is halogen,(C₁₋₈)alkyl, (C₁₋₈)alkoxy, O-alkylcarboxylate, O-aralkylcarboxylate,N-alkylcarboxamido, N-aralkylcarboxamido; or phenyl; s is 1 to 6; t is 0to 6; and u is 0 to 3. In some such embodiments, R⁵ has formula:

In other such embodiments, R⁵ is

including for example, the following structures:

In still other such embodiments, the compound has the formula

Compounds of formula I wherein X is CH₂; the ring containing X issaturated; CR^(i)R^(ii) is absent, R¹, R², R³ and R⁴ are hydrogen; andR⁵ is a group of the formula:

where R²¹ is hydrogen; (C₁₋₈)alkyl; benzyl; or phenyl; in which thebenzyl and phenyl groups are optionally mono- or independentlydi-substituted on the ring with R¹²; each t is independently 0 to 6; andu is 0 to 3. In some such embodiments, R⁵ has formula:

Compounds of formula I include those wherein R¹ and R² are hydrogen; nis 1; X together with an adjacent ring carbon and Z form a fusedcyclopropyl; CR^(i)R^(ii) is absent;

R³, R⁴ and R⁵ are independently hydrogen; alkyl; alkenyl; alkynyl;cycloalkyl; cycloalkylalkyl; bicycloalkyl; tricycloalkyl;alkylcycloalkyl; hydroxyalkyl; hydroxyalkylcycloalkyl;hydroxycycloalkyl; hydroxybicycloalkyl; hydroxytricycloalkyl;bicycloalkylalkyl; alkylbicycloalkyl; alkylthioalkyl;arylalkylthioalkyl; cycloalkenyl; aryl, aralkyl; heteroaryl;heteroarylalkyl; cycloheteroalkyl or cycloheteroalkylalkyl; alloptionally mono- or independently plurisubstituted with halogen, alkyl,polyhaloalkyl, alkoxy, haloalkoxy, polyhaloalkoxy, alkoxycarbonyl,alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, polycycloalkyl,heteroarylamino, arylamino, cycloheteroalkyl, cycloheteroalkylalkyl,hydroxy, hydroxyalkyl, nitro, cyano, amino, substituted amino,alkylamino, dialkylamino, thiol, alkylthio, alkylcarbonyl, acyl,alkoxycarbonyl, aminocarbonyl, alkynylaminocarbonyl, alkylaminocarbonyl,alkenylaminocarbonyl, alkylcarbonyloxy, alkylcarbonylamino,arylcarbonylamino, alkylsulfonylamino, alkylaminocarbonyl-amino,alkoxycarbonylamino, alkylsulfonyl, aminosulfinyl, aminosulfonyl,alkylsulfinyl, sulfonamido or sulfonyl; or

-   -   R⁴ and R⁵ together form —(CR²²R²³)_(m)— where m is 2 to 6, and        R²² and R²³ are independently hydrogen; hydroxyl; alkoxy; alkyl;        alkenyl; alkynyl; cycloalkyl; halo; amino; substituted amino;        cycloalkylalkyl; cycloalkenyl; aryl; arylalkyl; heteroaryl,        heteroarylalkyl; cycloheteroalkyl; cycloheteroalkylalkyl;        alkylcarbonylamino; arylcarbonylamino; alkoxycarbonyl-amino;        aryloxycarbonyl-amino; alkoxycarbonyl; aryloxycarbonyl; or        alkylaminocarbonylamino; or    -   R⁴ and R⁵ together with the atoms to which they are attached        form a 5 to 7 membered ring containing a total of 2 to 4        heteroatoms selected from N, O, S, SO, or SO₂; or    -   R⁴ and R⁵ together with the atoms to which they are attached        form a 4 to 8 membered cycloheteroalkyl ring wherein the        cycloheteroalkyl ring optionally has an aryl, heteroaryl or 3 to        7 membered cycloalkyl ring fused thereto.

In some embodiments of compounds of Formula I, R^(I), R², R³ and R⁴ arehydrogen; n is 1; X is CH₂; CR^(i)R^(ii) is absent; and R⁵ is aryl oraralkyl.

In some embodiments, compounds of formula I have the formula:

In other embodiments, compounds of formula I have the formula:

In still other embodiments, compounds of formula I have the formula:

In still other embodiments, compounds of formula I have the formula:

Compounds of formula I include those wherein,

if CR^(i)R^(ii) is present, R^(i) and R³ are hydrogen; R^(ii) and R⁴together form a 4 to 8 membered cyclic, polycyclic or heterocyclic ringsystem containing 1 to 3 heteroatoms selected from N, O, S, SO and SO₂,and includes single rings, fused bicyclic and tricyclic rings, which areoptionally mono- or independently plurisubstituted with any of thegroups set forth in (aa) or (bb) and R⁵ is any of the groups in (aa) or(bb); or

if CR^(i)R^(ii) is absent, then R³ is hydrogen; and R⁴ and R⁵ togetherwith the atoms to which they are attached form a 4 to 8 membered cyclic,polycyclic or heterocyclic ring system containing 1 to 3 heteroatomsselected from N, O, S, SO and SO₂, and includes single rings, fusedbicyclic and tricyclic rings, which are optionally mono- orindependently plurisubstituted with any of the groups set forth in (dd)or (ee); provided that when n is 1, X is CH₂, the ring containing X issaturated, and Z and R³ are hydrogen, R⁴ and R⁵ together are not—(CH₂)₂— or —(CH₂)₃—.

In some such embodiments, compounds of formula I have formula II:

wherein:

Y is O S, CHR²⁵ or NR²⁶;

k is 0 to 3 and m is 0 to 3 when Y is CHR²⁵;

k is 2 to 3 and m is 1 to 3 when Y is O or NR²⁶;

each R²⁴ is independently:

-   -   a) hydrogen;    -   b) (C₁₋₁₂)alkyl; (C₂₋₁₂)alkenyl; (C₂₋₁₂)alkynyl;        (C₃₋₁₂)cycloalkyl; or (C₃₋₁₂)cycloalkenyl; where the alkyl,        alkenyl, alkynyl, cycloalkyl and cycloalkenyl groups are        optionally mono- or independently plurisubstituted with R¹², and        where the alkyl, alkenyl, alkynyl portions include linear or        branched chains and may include cyclic portions;    -   c) aryl; or heteroaryl; where the aryl and heteroaryl groups are        optionally mono- or independently plurisubstituted with R¹²;    -   d) R¹¹(CH₂)_(p)— where R¹¹ is 2-oxopyrrolidinyl; (C₁₋₆)alkoxy;        phenyl; phenoxy; (C₁₋₈)cycloalkyl; [3.3.3] bicyclic carbocyclic        moiety; pyridinyl; naphthyl; cyclohexenyl; (C₁₋₈)alkylcarbonyl;        (C₃₋₁₂)cycloalkylcarbonyl; benzyl; benzoyl; pyrimidinyl;        phenylaminocarbonyl; alkylsulfonyl; phenylsulfonyl; or        adamantyl; where the cycloalkyl ring is optionally substituted        with hydroxy(C₁₋₆)alkyl; where the 2-oxopyrrolidinyl,        (C₁₋₆)alkoxy, phenyl, pyridinyl, benzyl, benzoyl, pyrimidinyl,        phenylaminocarbonyl, alkylsulfonyl, phenylsulfonyl, and naphthyl        groups are optionally mono- or independently di- or        independently trisubstituted with R¹²; where the phenoxy group        is optionally mono- or independently disubstituted with        (C₁₋₄)alkyl, (C₁₋₄)alkoxy, or halogen; and where the [3.3.3]        bicyclic carbocyclic moiety is optionally mono-or independently        plurisubstituted with (C₁₋₈)alkyl; p is 0 to 3; and    -   R¹² is halogen; trifluoromethyl; cyano; nitro; (C₁₋₆)alkyl;        (C₁₋₆)alkoxy; cycloalkyl; carboxy; acetamido; hydroxy;        hydroxy(C₁₋₆)alkyl; hydroxymethyl; trifluoromethoxy; sulfamoyl;        carbamoyl; sulfonamido; alkylsufonyl; phenylsulfonyl; aryl;        heteroaryl; where the aryl and heteroaryl groups are optionally        mono- or independently plurisubstituted with R⁷;    -   e) (R¹³)₂CH(CH₂)_(q)—, where R¹³ is phenyl; in which the phenyl        groups are independently optionally mono- or independently        disubstituted with R¹²; and q is 0 to 3;    -   f) a group of the formula:

where R¹⁴ and R¹⁵ are independently hydrogen; (C₁₋₈)alkyl;(C₁₋₆)alkylcarbonyl; (C₃₋₁₂)cycloalkyl ring; (C₃₋₁₂)cycloalkenyl ring;benzyl; benzoyl; pyridine; pyrimidine; phenyl; phenylamino-carbonyl;alkylsulfonyl; or phenylsulfonyl; where the cycloalkyl ring isoptionally substituted with hydroxy(C₁₋₆)alkyl, and where the benzyl,benzoyl, pyridine, pyrimidine, phenyl, phenylaminocarbonyl,alkylsulfonyl, and phenylsulfonyl groups are optionally mono- orindependently di-substituted with R¹²; or R¹⁴ and R¹⁵ together form a(C₃₋₁₂)cycloalkyl ring; and s is 1 to 6; or

-   -   -   g) a group of the formula:

where R²¹ is hydrogen; (C₁₋₈)alkyl; benzyl; or phenyl; in which thebenzyl and phenyl groups are optionally mono- or independentlydi-substituted on the ring with R¹²; and t is 1 to 6;

R²⁵ is:

-   -   a) hydrogen;    -   b) (C₁₋₁₂)alkyl; (C₂₋₁₂)alkenyl; (C₂₋₁₂)alkynyl;        (C₃₋₁₂)cycloalkyl; or (C₃₋₁₂)cycloalkenyl; where the alkyl,        alkenyl, alkynyl, cycloalkyl and cycloalkenyl groups are        optionally mono- or independently plurisubstituted with R¹², and        where the alkyl, alkenyl, alkynyl portions include linear or        branched chains and may include cyclic portions;    -   c) aryl; or heteroaryl; where the aryl and heteroaryl groups are        optionally mono- or independently plurisubstituted with R¹²;    -   d) R¹¹(CH₂)_(p)— where R¹¹ is 2-oxopyrrolidinyl; (C₁₋₆)alkoxy;        phenyl; phenoxy; (C₁₋₈)cycloalkyl; [3.3.3] bicyclic carbocyclic        moiety; pyridinyl; naphthyl; cyclohexenyl; (C₁₋₈)alkylcarbonyl;        (C₃₋₁₂)cycloalkylcarbonyl; benzyl; benzoyl; pyrimidinyl;        phenylaminocarbonyl; alkylsulfonyl; phenylsulfonyl; or        adamantyl; where the cycloalkyl ring is optionally substituted        with hydroxy(C₁₋₆)alkyl; where the 2-oxopyrrolidinyl,        (C₁₋₆)alkoxy, phenyl, pyridinyl, benzyl, benzoyl, pyrimidinyl,        phenylaminocarbonyl, alkylsulfonyl, phenylsulfonyl, and naphthyl        groups are optionally mono- or independently di- or        independently trisubstituted with R¹²; where the phenoxy group        is optionally mono- or independently disubstituted with        (C₁₋₄)alkyl, (C₁₋₄)alkoxy, or halogen; and where the [3.3.3]        bicyclic carbocyclic moiety is optionally mono-or independently        plurisubstituted with (C₁₋₈)alkyl; p is 0 to 3; and    -   R¹² is halogen; trifluoromethyl; cyano; nitro; (C₁₋₆)alkyl;        (C₁₋₆)alkoxy; cycloalkyl; carboxy; acetamido; hydroxy;        hydroxy(C₁₋₆)alkyl; hydroxymethyl; trifluoromethoxy; sulfamoyl;        carbamoyl; sulfonamido; alkylsufonyl; phenylsulfonyl; aryl;        heteroaryl; where the aryl and heteroaryl groups are optionally        mono- or independently plurisubstituted with R⁷;    -   e) (R¹³)₂CH(CH₂)_(q)—, where R¹³ is phenyl; in which the phenyl        groups are independently optionally mono- or independently        disubstituted with R¹²; and q is 0 to 3;    -   f) a group of the formula:

where R¹⁴ and R¹⁵ are independently hydrogen; (C₁₋₈)alkyl;(C₁₋₆)alkylcarbonyl; (C₃₋₁₂)cycloalkyl ring; (C₃₋₁₂)cycloalkenyl ring;benzyl; benzoyl; pyridine; pyrimidine; phenyl; phenylamino-carbonyl;alkylsulfonyl; or phenylsulfonyl; where the cycloalkyl ring isoptionally substituted with hydroxy(C₁₋₆)alkyl, and where the benzyl,benzoyl, pyridine, pyrimidine, phenyl, phenylaminocarbonyl,alkylsulfonyl, and phenylsulfonyl groups are optionally mono- orindependently di-substituted with R¹²; or R¹⁴ and R¹⁵ together form a(C₃₋₁₂)cycloalkyl ring; and t is 0 to 6; or

-   -   g) a group of the formula:

where R²¹ is hydrogen; (C₁₋₈)alkyl; benzyl; or phenyl; in which thebenzyl and phenyl groups are optionally mono- or independentlydi-substituted on the ring with R¹²; and t is 0 to 6; and

R²⁶ is:

-   -   a) hydrogen;    -   b) (C₁₋₁₂)alkyl; (C₂₋₁₂)alkenyl; (C₂₋₁₂)alkynyl;        (C₃₋₁₂)cycloalkyl; or (C₃₋₁₂)cycloalkenyl; where the alkyl,        alkenyl, alkynyl, cycloalkyl and cycloalkenyl groups are        optionally mono- or independently plurisubstituted with R¹², and        where the alkyl, alkenyl, alkynyl portions include linear or        branched chains and may include cyclic portions;    -   c) aryl; or heteroaryl; where the aryl and heteroaryl groups are        optionally mono- or independently plurisubstituted with R¹²;    -   d) R²⁷(CH₂)_(p)—, where R²⁷ is 2-oxopyrrolidinyl; (C₁₋₆)alkoxy;        phenyl; phenoxy; (C₁₋₈)cycloalkyl; [3.3.3] bicyclic carbocyclic        moiety; pyridinyl; naphthyl; cyclohexenyl; (C₁₋₈)alkylcarbonyl;        (C₃₋₁₂)cycloalkylcarbonyl; benzyl; benzoyl; pyrimidinyl;        phenylaminocarbonyl; alkylsulfonyl; phenylsulfonyl; or        adamantyl; where the cycloalkyl ring is optionally substituted        with hydroxy(C₁₋₆)alkyl; where the 2-oxopyrrolidinyl,        (C₁₋₆)alkoxy, phenyl, pyridinyl, benzyl, benzoyl, pyrimidinyl,        phenylaminocarbonyl, alkylsulfonyl, phenylsulfonyl, and naphthyl        groups are optionally mono- or independently di- or        independently trisubstituted with R¹²; where the phenoxy group        is optionally mono- or independently disubstituted with        (C₁₋₄)alkyl, (C₁₋₄)alkoxy, or halogen; and where the [3.3.3]        bicyclic carbocyclic moiety is optionally mono-or independently        plurisubstituted with (C₁₋₈)alkyl; p is 0 to 3; and    -   R¹² is halogen; trifluoromethyl; cyano; nitro; (C₁₋₆)alkyl;        (C₁₋₆)alkoxy; cycloalkyl; carboxy; acetamido; hydroxy;        hydroxy(C₁₋₆)alkyl; hydroxymethyl; trifluoromethoxy; sulfamoyl;        carbamoyl; sulfonamido; alkylsufonyl; phenylsulfonyl; aryl;        heteroaryl; where the aryl and heteroaryl groups are optionally        mono- or independently plurisubstituted with R⁷;    -   e) (R¹³)₂CH(CH₂)_(q)—, where R¹³ is phenyl, in which the phenyl        groups are independently optionally mono- or independently        disubstituted with R¹²; and q is 0 to 3;    -   f) a group of the formula:

where R¹⁴ and R¹⁵ are independently hydrogen; (C₁₋₈)alkyl;(C₁₋₆)alkylcarbonyl; (C₃₋₁₂)cycloalkyl ring; (C₃₋₁₂)cycloalkenyl ring;benzyl; benzoyl; pyridine; pyrimidine; phenyl; phenylamino-carbonyl;alkylsulfonyl; or phenylsulfonyl; where the cycloalkyl ring isoptionally substituted with hydroxy(C₁₋₆)alkyl, and where the benzyl,benzoyl, pyridine, pyrimidine, phenyl, phenylaminocarbonyl,alkylsulfonyl, and phenylsulfonyl groups are optionally mono- orindependently di-substituted with R¹²; or R¹⁴ and R¹⁵ together form a(C₃₋₁₂)cycloalkyl ring; and r is 0 or 2 to 6; or

-   -   g) a group of the formula:

where R²¹ is hydrogen; (C₁₋₈)alkyl; benzyl; or phenyl; in which thebenzyl and phenyl groups are optionally mono- or independentlydi-substituted on the ring with R¹²; and t is 0 or 2 to 6.

In some embodiments of compounds of formula II, X is CH₂; the ringcontaining X is saturated; and R¹, R² and R²⁵ are hydrogen. In otherembodiments of compounds of formula II, X is CH₂; the ring containing Xis saturated; R¹, R² and R²⁵ are hydrogen; and R²⁴ is hydrogen, providedthat if k, n, and m are each 1, and Y is CHR²⁵, Z is not H. In stillother embodiments of compounds of formula II, X is CH₂; the ringcontaining X is saturated; R¹, R² and R²⁵ are hydrogen; and R²⁴ is(C₁₋₁₂)alkyl; (C₂₋₁₂)alkenyl; (C₂₋₁₂)alkynyl; (C₃₋₁₂)cycloalkyl; or(C₃₋₁₂)cycloalkenyl; where the alkyl, alkenyl, alkynyl, cycloalkyl andcycloalkenyl groups are optionally mono- or independentlyplurisubstituted with R¹², and where the alkyl, alkenyl, alkynylportions include linear or branched chains and may include cyclicportions. In some embodiments of compounds of formula II, X is CH₂; thering containing X is saturated; R¹, R² and R²⁵ are hydrogen; and R²⁴ isphenyl optionally mono- or independently plurisubstituted with R¹².

Compounds of formula II include those wherein X is CH₂; the ringcontaining X is saturated; R¹, R² and R²⁵ are hydrogen; and R²⁴ isR¹¹(CH₂)_(p)— where R¹¹ is 2-oxopyrrolidinyl; (C₁₋₆)alkoxy; phenyl;phenoxy; (C₁₋₈)cycloalkyl; [3.3.3] bicyclic carbocyclic moiety;pyridinyl; naphthyl; cyclohexenyl; (C₁₋₈)alkylcarbonyl;(C₃₋₁₂)cycloalkylcarbonyl; benzyl; benzoyl; pyrimidinyl;phenylaminocarbonyl; alkylsulfonyl; phenylsulfonyl; or adamantyl; wherethe cycloalkyl ring is optionally substituted with hydroxy(C₁₋₆)alkyl;where the 2-oxopyrrolidinyl, (C₁₋₆)alkoxy, phenyl, pyridinyl, benzyl,benzoyl, pyrimidinyl, phenylaminocarbonyl, alkylsulfonyl,phenylsulfonyl, and naphthyl groups are optionally mono- orindependently di- or independently trisubstituted with R¹²; where thephenoxy group is optionally mono- or independently disubstituted with(C₁₋₄)alkyl, (C₁₋₄)alkoxy, or halogen; and where the [3.3.3] bicycliccarbocyclic moiety is optionally mono-or independently plurisubstitutedwith (C₁₋₈)alkyl; p is 0 to 3; and R¹² is halogen; trifluoromethyl;cyano; nitro; (C₁₋₆)alkyl; (C₁₋₆)alkoxy; cycloalkyl; carboxy; acetamido;hydroxy; hydroxy(C₁₋₆)alkyl; hydroxymethyl; trifluoromethoxy; sulfamoyl;carbamoyl; sulfonamido; alkylsufonyl; phenylsulfonyl; aryl; heteroaryl;where the aryl and heteroaryl groups are optionally mono- orindependently plurisubstituted with R⁷.

In certain embodiments of compounds of formula II, X is CH₂; the ringcontaining X is saturated; R¹, R² and R²⁵ are hydrogen; and R²⁴ is(R¹³)₂CH(CH₂)_(q)—, where R¹³ is phenyl; in which the phenyl groups areindependently optionally mono- or independently disubstituted with R¹²;and q is 0 to 3.

In other embodiments of compounds of formula II, X is CH₂; the ringcontaining X is saturated; R¹, R² and R²⁵ are hydrogen; and R²⁴ is agroup of the formula:

where R¹⁴ and R¹⁵ are independently hydrogen; (C₁₋₈)alkyl;(C₁₋₆)alkylcarbonyl; (C₃₋₁₂)cycloalkyl ring; (C₃₋₁₂)cycloalkenyl ring;benzyl; benzoyl; pyridine; pyrimidine; phenyl; phenylamino-carbonyl;alkylsulfonyl; or phenylsulfonyl; where the cycloalkyl ring isoptionally substituted with hydroxy(C₁₋₆)alkyl, and where the benzyl,benzoyl, pyridine, pyrimidine, phenyl, phenylaminocarbonyl,alkylsulfonyl, and phenylsulfonyl groups are optionally mono- orindependently di-substituted with R¹²; or R¹⁴ and R¹⁵ together form a(C₃₋₁₂)cycloalkyl ring; and s is 1 to 6.

In some embodiments of compounds of formula II, X is CH₂; the ringcontaining X is saturated; R¹, R² and R²⁵ are hydrogen; and R²⁴ is agroup of the formula:

where R²¹ is hydrogen; (C₁₋₈)alkyl; benzyl; or phenyl; in which thebenzyl and phenyl groups are optionally mono- or independentlydi-substituted on the ring with R¹²; and t is 1 to 6.

Compounds of formula II include those wherein X is CH₂; the ringcontaining X is saturated; R¹, R² and R²⁴ are hydrogen. In someembodiments of compounds of formula II, X is CH₂; the ring containing Xis saturated; R¹, R², R²⁴ are hydrogen; and R²⁵ is (C₁₋₁₂)alkyl;(C₂₋₁₂)alkenyl; (C₂₋₁₂)alkynyl; (C₃₋₁₂)cycloalkyl; or(C₃₋₁₂)cycloalkenyl; where the alkyl, alkenyl, alkynyl, cycloalkyl andcycloalkenyl groups are optionally mono- or independentlyplurisubstituted with R¹², and where the alkyl, alkenyl, alkynylportions include linear or branched chains and may include cyclicportions. In other embodiments of compounds of formula II, X is CH₂; thering containing X is saturated; R¹, R², R²⁴ are hydrogen; and R²⁵ isphenyl optionally mono- or independently plurisubstituted with R¹².

Compounds of formula II include those wherein X is CH₂; the ringcontaining X is saturated; R¹, R², R²⁴ are hydrogen; and R²⁵ isR¹¹(CH₂)_(p)— where R¹¹ is 2-oxopyrrolidinyl, (C₁₋₆)alkoxy, phenyl;phenoxy; (C₁₋₈)cycloalkyl; [3.3.3] bicyclic carbocyclic moiety;pyridinyl; naphthyl; cyclohexenyl; or adamantyl; where the2-oxopyrrolidinyl, (C₁₋₆)alkoxy, phenyl, pyridinyl, and naphthyl groupsare optionally mono- or independently di- or independentlytrisubstituted with R¹²; where the phenoxy group is optionally mono- orindependently disubstituted with (C₁₋₄)alkyl, (C₁₋₄)alkoxy, or halogen;and where the [3.3.3] bicyclic carbocyclic moiety is optionally mono-orindependently plurisubstituted with (C₁₋₈)alkyl; p is 0 to 3; and R¹² ishalogen; trifluoromethyl; cyano; nitro; (C₁₋₆)alkyl; (C₁₋₆)alkoxy;cycloalkyl; carboxy; acetamido; hydroxy; hydroxy(C₁₋₆)alkyl;hydroxymethyl; trifluoromethoxy; sulfamoyl; carbamoyl; sulfonamido;alkylsufonyl; phenylsulfonyl; aryl; heteroaryl; where the aryl andheteroaryl groups are optionally mono- or independently plurisubstitutedwith R⁷.

In other embodiments of compounds of formula II, X is CH₂; the ringcontaining X is saturated; R¹, R², R²⁴ are hydrogen; and R²⁵ is(R¹³)₂CH(CH₂)_(q)—, where R¹³ is phenyl; in which the phenyl groups areindependently optionally mono- or independently disubstituted with R¹²;and q is 0 to 3.

Compounds of formula II include those wherein X is CH₂; the ringcontaining X is saturated; R¹, R², R²⁴ are hydrogen; and R²⁵ is a groupof the formula:

where R¹⁴ and R¹⁵ are independently hydrogen; (C₁₋₈)alkyl;(C₁₋₆)alkylcarbonyl; (C₃₋₁₂)cycloalkyl ring; (C₃₋₁₂)cycloalkenyl ring;benzyl; benzoyl; pyridine; pyrimidine; phenyl; phenylamino-carbonyl;alkylsulfonyl; or phenylsulfonyl; where the cycloalkyl ring isoptionally substituted with hydroxy(C₁₋₆)alkyl, and where the benzyl,benzoyl, pyridine, pyrimidine, phenyl, phenylaminocarbonyl,alkylsulfonyl, and phenylsulfonyl groups are optionally mono- orindependently di-substituted with R¹²; or R¹⁴ and R¹⁵ together form a(C₃₋₁₂)cycloalkyl ring; and t is 0 to 6.

In some embodiments of compounds of formula II, X is CH₂; the ringcontaining X is saturated; R¹, R², R²⁴ are hydrogen; and R²⁵ is a groupof the formula:

where R²¹ is hydrogen; (C₁₋₈)alkyl; benzyl; or phenyl; in which thebenzyl and phenyl groups are optionally mono- or independentlydi-substituted on the ring with R¹²; and t is 0 to 6. In otherembodiments of compounds of formula II, X is CH₂; the ring containing Xis saturated; R¹, R², R²⁴ and R²⁶ are hydrogen. In still otherembodiments of compounds of formula II, X is CH₂; the ring containing Xis saturated; R¹, R², R²⁴ are hydrogen; and R²⁶ is (C₁₋₁₂)alkyl;(C₂₋₁₂)alkenyl; (C₂₋₁₂)alkynyl; (C₃₋₁₂)cycloalkyl; or(C₃₋₁₂)cycloalkenyl; where the alkyl, alkenyl, alkynyl, cycloalkyl andcycloalkenyl groups are optionally mono- or independentlyplurisubstituted with R¹², and where the alkyl, alkenyl, alkynylportions include linear or branched chains and may include cyclicportions. Compounds of formula II include those wherein X is CH₂; thering containing X is saturated; R¹, R², R²⁴ are hydrogen; and R²⁶ isphenyl optionally mono- or independently plurisubstituted with R¹².

Compounds of formula II wherein X is CH₂; the ring containing X issaturated; R¹, R², R²⁴ are hydrogen; and R²⁶ is R²⁷(CH₂)_(p)—, where R²⁷is 2-oxopyrrolidinyl; (C₁₋₆)alkoxy; phenyl; phenoxy; (C₁₋₈)cycloalkyl;[3.3.3] bicyclic carbocyclic moiety; pyridinyl; naphthyl; cyclohexenyl;(C₁₋₈)alkylcarbonyl; (C₃₋₁₂)cycloalkylcarbonyl; benzyl; benzoyl;pyrimidinyl; phenylaminocarbonyl; alkylsulfonyl; phenylsulfonyl; oradamantyl; where the cycloalkyl ring is optionally substituted withhydroxy(C₁₋₆)alkyl; where the 2-oxopyrrolidinyl, (C₁₋₆)alkoxy, phenyl,pyridinyl, benzyl, benzoyl, pyrimidinyl, phenylaminocarbonyl,alkylsulfonyl, phenylsulfonyl, and naphthyl groups are optionally mono-or independently di- or independently trisubstituted with R¹²; where thephenoxy group is optionally mono- or independently disubstituted with(C₁₋₄)alkyl, (C₁₋₄)alkoxy, or halogen; and where the [3.3.3] bicycliccarbocyclic moiety is optionally mono- or independently plurisubstitutedwith (C₁₋₈)alkyl; p is 0 to 3; and R¹² is halogen; trifluoromethyl;cyano; nitro; (C₁₋₆)alkyl; (C₁₋₆)alkoxy; cycloalkyl; carboxy; acetamido;hydroxy; hydroxy(C₁₋₆)alkyl; hydroxymethyl; trifluoromethoxy; sulfamoyl;carbamoyl; sulfonamido; alkylsufonyl; phenylsulfonyl; aryl; heteroaryl;where the aryl and heteroaryl groups are optionally mono- orindependently plurisubstituted with R⁷; and p is 0 to 3.

Compounds of formula II include those wherein X is CH₂; the ringcontaining X is saturated; R¹, R², R²⁴ are hydrogen; and R²⁶ is(R¹³)₂CH(CH₂)_(q)—; where R¹³ is phenyl, in which the phenyl groups areindependently optionally mono- or independently disubstituted with R¹²;and q is 0 to 3.

In some embodiments of compounds of formula II, X is CH₂; the ringcontaining X is saturated; R¹, R², R²⁴ are hydrogen; and R²⁶ is a groupof the formula:

where R¹⁴ and R¹⁵ are independently hydrogen; (C₁₋₈)alkyl;(C₁₋₆)alkylcarbonyl; (C₃₋₁₂)cycloalkyl ring; (C₃₋₁₂)cycloalkenyl ring;benzyl; benzoyl; pyridine; pyrimidine; phenyl; phenylamino-carbonyl;alkylsulfonyl; or phenylsulfonyl; where the cycloalkyl ring isoptionally substituted with hydroxy(C₁₋₆)alkyl, and where the benzyl,benzoyl, pyridine, pyrimidine, phenyl, phenylaminocarbonyl,alkylsulfonyl, and phenylsulfonyl groups are optionally mono- orindependently di-substituted with R¹²; or R¹⁴ and R¹⁵ together form a(C₃₋₁₂)cycloalkyl ring; and r is 0 or 2 to 6.

In other embodiments of compounds of formula II, X is CH₂; the ringcontaining X is saturated; R¹, R², R²⁴ are hydrogen; and R²⁶ is a groupof the formula:

where R²¹ is hydrogen; (C₁₋₈)alkyl; benzyl; or phenyl; in which thebenzyl and phenyl groups are optionally mono- or independentlydi-substituted on the ring with R¹²; and t is 0 or 2 to 6.

Compounds of formula II include those that have the formula:

In some such embodiments, R²⁵ is phenyl optionally mono- orindependently plurisubstituted with R¹².

In other embodiments of compounds of formula II, the compound has theformula:

Compounds of formula II also include those that have the formula:

wherein:

R²⁸ and R²⁹ are each independently hydrogen, hydroxy, alkyl, alkoxy,aryloxy, or halogen.

In some embodiments of compounds of formula I wherein CR^(i)R^(ii) ispresent, the compound has formula III:

wherein:

Y is O, S, CHR²⁵ or NR²⁶;

k is 0 to 3 and m is 0 to 3 when Y is CHR²⁵;

k is 1 to 3 and m is 0 to 3 when Y is NR²⁶;

k is 1 to 3 and m is 0 to 3 when Y is O;

R is

-   -   a) hydrogen;    -   b) (C₁₋₁₂)alkyl; (C₂₋₁₂)alkenyl; (C₂₋₁₂)alkynyl;        (C₃₋₁₂)cycloalkyl; or (C₃₋₁₂)cycloalkenyl; where the alkyl,        alkenyl, alkynyl, cycloalkyl and cycloalkenyl groups are        optionally mono- or independently plurisubstituted with R⁶, and        where the alkyl, alkenyl, alkynyl portions include linear or        branched chains and may include cyclic portions;    -   R⁶ is (C₁₋₆)alkyl; (C₁₋₆)alkoxy; cycloalkyl; carboxy; acetamido;        cyano; nitro; halogen; hydroxy; hydroxy(C₁₋₆)alkyl;        hydroxymethyl; trifluoromethyl; trifluoromethoxy; sulfamoyl;        sulfonamido; carbamoyl; aryl; heteroaryl; where the aryl and        heteroaryl groups are optionally mono- or independently        plurisubstituted with R⁷; amino, where the amino group is        optionally mono- or independently plurisubstituted with R⁸;        —SOR⁸; —SO₂R⁸; —COR⁸; —CO2R⁸, —CONHR⁸; —CON(R⁸)₂; —OR⁸; or        —S—R⁸;    -   R⁷ is halogen; (C₁₋₁₀)alkyl; (C₁₋₁₀)alkoxy; (C₁₋₁₀)alkylamino;        (C₁₋₁₀) dialkylamino; benzyl; benzyloxy; hydroxyl(C₁₋₆)alkyl;        hydroxymethyl; nitro; trifluoromethyl; trifluoromethoxy;        trifluoromethylthio; N-hydroxyimino; cyano; carboxy; acetamido;        hydroxy; sulfamoyl; sulfonamido; or carbamoyl;    -   R⁸ is (C₁₋₁₀)alkyl; (C₂₋₁₀)alkenyl; (C₂₋₁₀)alkynyl;        (C₃₋₁₀)cycloalkyl; (C₅₋₁₀)cycloalkenyl; benzyl; phenethyl; aryl;        or heteroaryl; where the alkyl, alkenyl, alkynyl, cycloalkyl,        cycloalkenyl groups are optionally mono- or independently        plurisubstituted with aryl or heteroaryl where the aryl and        heteroaryl groups are optionally mono- or independently        plurisubstituted with R⁷; and where the aryl and heteroaryl        groups are optionally mono- or independently plurisubstituted        with R⁷;    -   c) aryl optionally fused to a (C₃₋₁₀)cycloalkyl; or heteroaryl        optionally fused to a (C₃₋₁₀)cycloalkyl; where the aryl and        heteroaryl groups are optionally mono- or independently        plurisubstituted with R⁷;    -   d) indanyl; 1,2,3,4-tetrahydronaphthyl; (CH₂)_(j)adamantyl in        which j is 0-3; or a [2.2.1] or [3.1.1] bicyclic carbocyclic        moiety, including (4-pentylbicyclo[2.2.2]oct-1-yl)amine; where        the indanyl, 1,2,3,4-tetrahydronaphthyl, (CH₂)_(j) adamantyl,        and [2.2.1] or [3.1.1] bicyclic carbocyclic moieties are        optionally mono- or independently plurisubstituted with hydroxy,        (C₁₋₈)alkyl, (C₁₋₈)alkoxy, (C₁₋₈)alkanoyloxy, or R⁹R¹⁰N—CO—O—,        where R⁹ and R¹⁰ are independently (C₁₋₈)alkyl, or phenyl, where        the alkyl and phenyl groups are optionally mono- or        independently plurisubstituted with (C₁₋₈)alkyl, (C₁₋₈)alkoxy,        halogen, or trifluoromethyl, or R⁹ and R¹⁰ together are        (C₃₋₆)alkylene;    -   e) R¹¹(CH₂)_(p)— where R¹¹ is 2-oxopyrrolidinyl; (C₁₋₆)alkoxy;        phenyl; phenoxy; (C₁₋₈)cycloalkyl; [3.3.3] bicyclic carbocyclic        moiety; pyridinyl; naphthyl; cyclohexenyl; or adamantyl; where        the 2-oxopyrrolidinyl, (C₁₋₆)alkoxy, phenyl, pyridinyl, and        naphthyl groups are optionally mono- or independently di- or        independently trisubstituted with R¹²; where the phenoxy group        is optionally mono- or independently disubstituted with        (C₁₋₄)alkyl, (C₁₋₄)alkoxy, or halogen; and where the [3.3.3]        bicyclic carbocyclic moiety is optionally mono-or independently        plurisubstituted with (C₁₋₈)alkyl; and p is 0 to 3;    -   R¹² is halogen; trifluoromethyl; cyano; nitro; (C₁₋₆)alkyl;        (C₁₋₆)alkoxy; cycloalkyl; carboxy; acetamido; hydroxy;        hydroxy(C₁₋₆)alkyl; hydroxymethyl; trifluoromethoxy; sulfamoyl;        carbamoyl; sulfonamido; alkylsufonyl; phenyl sulfonyl; aryl;        heteroaryl; where the aryl and heteroaryl groups are optionally        mono- or independently plurisubstituted with R⁷;    -   f) (R¹³)₂CH(CH₂)_(q)—, where R¹³ is phenyl; in which the phenyl        groups are independently optionally mono- or independently        disubstituted with R¹²; and q is 0 to 3;    -   g) a group of the formula:

-   -   where R¹⁴ and R¹⁵ are independently hydrogen; (C₁₋₈)alkyl;        (C₁₋₆)alkylcarbonyl; (C₃₋₁₂)cycloalkyl ring; (C₃₋₁₂)cycloalkenyl        ring; benzyl; benzoyl; pyridine; pyrimidine; phenyl;        phenylamino-carbonyl; alkylsulfonyl; or phenylsulfonyl; where        the cycloalkyl ring is optionally substituted with        hydroxy(C₁₋₆)alkyl, and where the benzyl, benzoyl, pyridine,        pyrimidine, phenyl, phenylaminocarbonyl, alkylsulfonyl, and        phenylsulfonyl groups are optionally mono- or independently        di-substituted with R¹²; or R¹⁴ and R¹⁵ together form a        (C₃₋₁₂)cycloalkyl ring; and r is 2 to 6;    -   h) a group of the formula:

-   -   where R¹⁶ and R¹⁷ are each independently hydrogen; (C₁₋₈)alkyl;        (C₁₋₆)alkylcarbonyl; di-(C₁₋₆)alkylaminocarbonyl; benzyl;        benzoyl; pyridine; pyrimidine; phenyl; phenylaminocarbonyl;        alkylsulfonyl; or phenylsulfonyl; where the benzyl, benzoyl,        pyridine, pyrimidine, phenyl, phenylaminocarbonyl,        alkylsulfonyl, and phenylsulfonyl groups are optionally mono- or        independently di-substituted with R¹²; or R¹⁶ and R¹⁷ together        form a (C₃₋₁₂)cycloalkyl ring; and s is 1 to 6;    -   i) a group of the formula:

-   -   where R¹⁸ and R¹⁹ are independently hydrogen; (C₁₋₈)alkyl;        (C₁₋₆)alkylcarbonyl; di-(C₁₋₆)alkylaminocarbonyl; benzyl;        benzothiazole; benzoyl; pyridine; pyrimidine; phenyl;        phenylaminocarbonyl; alkylsulfonyl; or phenylsulfonyl; where the        benzyl, benzoyl, benzothiazole, pyridine, pyrimidine, phenyl,        phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups        are optionally mono- or independently di-substituted with R¹²;        or R¹⁸ and R¹⁹ together form a (C₃₋₁₂)cycloalkyl ring; each t is        independently 0 to 6; and u is 0 to 3;    -   j) a group of the formula:

(phenyl-CH₂—C(CH₃)₂—),

-   -   where the phenyl group is optionally mono- or independently        plurisubstituted with R¹²;    -   k) a group of the formula:

where R²⁰ is hydrogen; (C₁₋₈)alkyl; (C₁₋₆)alkylcarbonyl;di-(C₁₋₆)alkylaminocarbonyl; (C₃₋₈)cycloalkylcarbonyl; benzyl; benzoyl;(C₁₋₆)alkyloxycarbonyl; arlkyloxycarbonyl, pyridine; pyrimidine; phenyl;phenyl substituted thiazole ring; phenylaminocarbonyl; alkylsulfonyl; orphenylsulfonyl; where the benzyl, benzoyl, pyridine, pyrimidine, phenyl,phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups areoptionally mono- or independently di-substituted with R¹²; R_(x) ishydrogen; (C₁₋₈)alkyl; (C₃₋₁₂)cycloalkyl; benzyl; phenyl; where thebenzyl and phenyl, groups are optionally mono- or independentlydi-substituted on the ring with R¹²; R_(y) is absent or is halogen,(C₁₋₈)alkyl, (C₁₋₈)alkoxy, O-alkylcarboxylate, O-aralkylcarboxylate,N-alkylcarboxamido, N-aralkylcarboxamido; or phenyl; s is 1 to 6; t is 0to 6; and u is 0 to 3; or

-   -   l) a group of the formula:

-   -   where R²¹ is hydrogen; (C₁₋₈)alkyl; benzyl; or phenyl; in which        the benzyl and phenyl groups are optionally mono- or        independently di-substituted on the ring with R¹²; each t is        independently 0 to 6; and u is 0 to 3;

each R²⁴ is independently:

-   -   a) hydrogen;    -   b) (C₁₋₁₂)alkyl; (C₂₋₁₂)alkenyl; (C₂₋₁₂)alkynyl;        (C₃₋₁₂)cycloalkyl; or (C₃₋₁₂)cycloalkenyl; where the alkyl,        alkenyl, alkynyl, cycloalkyl and cycloalkenyl groups are        optionally mono- or independently plurisubstituted with R¹², and        where the alkyl, alkenyl, alkynyl portions include linear or        branched chains and may include cyclic portions;    -   c) aryl; or heteroaryl; where the aryl and heteroaryl groups are        optionally mono- or independently plurisubstituted with R¹²;    -   d) R¹¹(CH₂)_(p)— where R¹¹ is 2-oxopyrrolidinyl; (C₁₋₆)alkoxy;        phenyl; phenoxy; (C₁₋₈)cycloalkyl; [3.3.3] bicyclic carbocyclic        moiety; pyridinyl; naphthyl; cyclohexenyl; (C₁₋₈)alkylcarbonyl;        (C₃₋₁₂)cycloalkylcarbonyl; benzyl; benzoyl; pyrimidinyl;        phenylaminocarbonyl; alkylsulfonyl; phenylsulfonyl; or        adamantyl; where the cycloalkyl ring is optionally substituted        with hydroxy(C₁₋₆)alkyl; where the 2-oxopyrrolidinyl,        (C₁₋₆)alkoxy, phenyl, pyridinyl, benzyl, benzoyl, pyrimidinyl,        phenylaminocarbonyl, alkylsulfonyl, phenylsulfonyl, and naphthyl        groups are optionally mono- or independently di- or        independently trisubstituted with R¹²; where the phenoxy group        is optionally mono- or independently disubstituted with        (C₁₋₄)alkyl, (C₁₋₄)alkoxy, or halogen; and where the [3.3.3]        bicyclic carbocyclic moiety is optionally mono-or independently        plurisubstituted with (C₁₋₈)alkyl; p is 0 to 3; and

R¹² is halogen; trifluoromethyl; cyano; nitro; (C₁₋₆)alkyl;(C₁₋₆)alkoxy; cycloalkyl; carboxy; acetamido; hydroxy;hydroxy(C₁₋₆)alkyl; hydroxymethyl; trifluoromethoxy; sulfamoyl;carbamoyl; sulfonamido; alkylsufonyl; phenylsulfonyl; aryl; heteroaryl;where the aryl and heteroaryl groups are optionally mono- orindependently plurisubstituted with R⁷;

-   -   e) (R¹³)₂CH(CH₂)_(q)—, where R¹³ is phenyl; in which the phenyl        groups are independently optionally mono- or independently        disubstituted with R¹²; and q is 0 to 3;    -   f) a group of the formula:

where R¹⁴ and R¹⁵ are independently hydrogen; (C₁₋₈)alkyl;(C₁₋₆)alkylcarbonyl; (C₃₋₁₂)cycloalkyl ring; (C₃₋₁₂)cycloalkenyl ring;benzyl; benzoyl; pyridine; pyrimidine; phenyl; phenylamino-carbonyl;alkylsulfonyl; or phenylsulfonyl; where the cycloalkyl ring isoptionally substituted with hydroxy(C₁₋₆)alkyl, and where the benzyl,benzoyl, pyridine, pyrimidine, phenyl, phenylaminocarbonyl,alkylsulfonyl, and phenylsulfonyl groups are optionally mono- orindependently di-substituted with R¹²; or R¹⁴ and R¹⁵ together form a(C₃₋₁₂)cycloalkyl ring; and s is 0 to 6; or

-   -   g) a group of the formula:

where R²¹ is hydrogen; (C₁₋₈)alkyl; benzyl; or phenyl; in which thebenzyl and phenyl groups are optionally mono- or independentlydi-substituted on the ring with R¹²; and t is 0 to 6;

R²⁵ is:

-   -   a) hydrogen;    -   b) (C₁₋₁₂)alkyl; (C₂₋₁₂)alkenyl; (C₂₋₁₂)alkynyl;        (C₃₋₁₂)cycloalkyl; or (C₃₋₁₂)cycloalkenyl; where the alkyl,        alkenyl, alkynyl, cycloalkyl and cycloalkenyl groups are        optionally mono- or independently plurisubstituted with R¹², and        where the alkyl, alkenyl, alkynyl portions include linear or        branched chains and may include cyclic portions;    -   c) aryl; or heteroaryl; where the aryl and heteroaryl groups are        optionally mono- or independently plurisubstituted with R¹²;    -   d) R¹¹(CH₂)_(p)— where R¹¹ is 2-oxopyrrolidinyl; (C₁₋₆)alkoxy;        phenyl; phenoxy; (C₁₋₈)cycloalkyl; [3.3.3] bicyclic carbocyclic        moiety; pyridinyl; naphthyl; cyclohexenyl; (C₁₋₈)alkylcarbonyl;        (C₃₋₁₂)cycloalkylcarbonyl; benzyl; benzoyl; pyrimidinyl;        phenylaminocarbonyl; alkylsulfonyl; phenylsulfonyl; or        adamantyl; where the cycloalkyl ring is optionally substituted        with hydroxy(C₁₋₆)alkyl; where the 2-oxopyrrolidinyl,        (C₁₋₆)alkoxy, phenyl, pyridinyl, benzyl, benzoyl, pyrimidinyl,        phenylaminocarbonyl, alkylsulfonyl, phenylsulfonyl, and naphthyl        groups are optionally mono- or independently di- or        independently trisubstituted with R¹²; where the phenoxy group        is optionally mono- or independently disubstituted with        (C₁₋₄)alkyl, (C₁₋₄)alkoxy, or halogen; and where the [3.3.3]        bicyclic carbocyclic moiety is optionally mono-or independently        plurisubstituted with (C₁₋₈)alkyl; p is 0 to 3; and    -   R¹² is halogen; trifluoromethyl; cyano; nitro; (C₁₋₆)alkyl;        (C₁₋₆)alkoxy; cycloalkyl; carboxy; acetamido; hydroxy;        hydroxy(C₁₋₆)alkyl; hydroxymethyl; trifluoromethoxy; sulfamoyl;        carbamoyl; sulfonamido; alkylsufonyl; phenylsulfonyl; aryl;        heteroaryl; where the aryl and heteroaryl groups are optionally        mono- or independently plurisubstituted with R²;    -   e) (R¹³)₂CH(CH₂)_(q)—, where R¹³ is phenyl; in which the phenyl        groups are independently optionally mono- or independently        disubstituted with R¹²; and q is 0 to 3;    -   f) a group of the formula:

where R¹⁴ and R¹⁵ are independently hydrogen; (C₁₋₈)alkyl;(C₁₋₆)alkylcarbonyl; (C₃₋₁₂)cycloalkyl ring; (C₃₋₁₂)cycloalkenyl ring;benzyl; benzoyl; pyridine; pyrimidine; phenyl; phenylamino-carbonyl;alkylsulfonyl; or phenylsulfonyl; where the cycloalkyl ring isoptionally substituted with hydroxy(C₁₋₆)alkyl, and where the benzyl,benzoyl, pyridine, pyrimidine, phenyl, phenylaminocarbonyl,alkylsulfonyl, and phenylsulfonyl groups are optionally mono- orindependently di-substituted with R¹²; or R¹⁴ and R¹⁵ together form a(C₃₋₁₂)cycloalkyl ring; and t is 0 to 6; or

-   -   g) a group of the formula:

where R²¹ is hydrogen; (C₁₋₈)alkyl; benzyl; or phenyl; in which thebenzyl and phenyl groups are optionally mono- or independentlydi-substituted on the ring with R¹²; and t is 0 to 6; and

R26 i_(s:)

-   -   a) hydrogen;    -   b) (C₁₋₁₂)alkyl; (C₂₋₁₂)alkenyl; (C₂₋₁₂)alkynyl;        (C₃₋₁₂)cycloalkyl; or (C₃₋₁₂)cycloalkenyl; where the alkyl,        alkenyl, alkynyl, cycloalkyl and cycloalkenyl groups are        optionally mono- or independently plurisubstituted with R¹², and        where the alkyl, alkenyl, alkynyl portions include linear or        branched chains and may include cyclic portions;    -   c) aryl; or heteroaryl; where the aryl and heteroaryl groups are        optionally mono- or independently plurisubstituted with R¹²;    -   d) R²⁷(CH₂)_(p)—, where R²⁷ is 2-oxopyrrolidinyl; (C₁₋₆)alkoxy;        phenyl; phenoxy; (C₁₋₈)cycloalkyl; [3.3.3] bicyclic carbocyclic        moiety; pyridinyl; naphthyl; cyclohexenyl; (C₁₋₈)alkylcarbonyl;        (C₃₋₁₂)cycloalkylcarbonyl; benzyl; benzoyl; pyrimidinyl;        phenylaminocarbonyl; alkylsulfonyl; phenylsulfonyl; or        adamantyl; where the cycloalkyl ring is optionally substituted        with hydroxy(C₁₋₆)alkyl; where the 2-oxopyrrolidinyl,        (C₁₋₆)alkoxy, phenyl, pyridinyl, benzyl, benzoyl, pyrimidinyl,        phenylaminocarbonyl, alkylsulfonyl, phenylsulfonyl, and naphthyl        groups are optionally mono- or independently di- or        independently trisubstituted with R¹²; where the phenoxy group        is optionally mono- or independently disubstituted with        (C₁₋₄)alkyl, (C₁₋₄)alkoxy, or halogen; and where the [3.3.3]        bicyclic carbocyclic moiety is optionally mono-or independently        plurisubstituted with (C₁₋₈)alkyl; p is 0 to 3; and    -   R¹² is halogen; trifluoromethyl; cyano; nitro; (C₁₋₆)alkyl;        (C₁₋₆)alkoxy; cycloalkyl; carboxy; acetamido; hydroxy;        hydroxy(C₁₋₆)alkyl; hydroxymethyl; trifluoromethoxy; sulfamoyl;        carbamoyl; sulfonamido; alkylsufonyl; phenylsulfonyl; aryl;        heteroaryl; where the aryl and heteroaryl groups are optionally        mono- or independently plurisubstituted with R⁷;    -   e) (R¹³)₂CH(CH₂)_(q)—, where R¹³ is phenyl, in which the phenyl        groups are independently optionally mono- or independently        disubstituted with R¹²; and q is 0 to 3;    -   f) a group of the formula:

where R¹⁴ and R¹⁵ are independently hydrogen; (C₁₋₈)alkyl;(C₁₋₆)alkylcarbonyl; (C₃₋₁₂)cycloalkyl ring; (C₃₋₁₂)cycloalkenyl ring;benzyl; benzoyl; pyridine; pyrimidine; phenyl; phenylamino-carbonyl;cycloalkenyl ring; benzyl; benzoyl; pyridine; pyrimidine; phenyl;phenylamino-carbonyl; alkylsulfonyl; or phenylsulfonyl; where thecycloalkyl ring is optionally substituted with hydroxy(C₁₋₆)alkyl, andwhere the benzyl, benzoyl, pyridine, pyrimidine, phenyl,phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups areoptionally mono- or independently di-substituted with R¹²; or R¹⁴ andR¹⁵ together form a (C₃₋₁₂)cycloalkyl ring; and r is 0 or 2 to 6; or

-   -   g) a group of the formula:

where R²¹ is hydrogen; (C₁₋₈)alkyl; benzyl; or phenyl; in which thebenzyl and phenyl groups are optionally mono- or independentlydi-substituted on the ring with R¹²; and t is 0 or 2 to 6.

Compounds of formula III include those wherein X is CH₂; the ringcontaining X is saturated; and R¹, R² and R²⁵ are hydrogen; thosewherein X is CH₂; the ring containing X is saturated; R¹, R² and R²⁵ arehydrogen; and R²⁴ is hydrogen; and those wherein X is CH₂; the ringcontaining X is saturated; R¹, R² and R²⁵ are hydrogen; and R²⁴ is(C₁₋₁₂)alkyl; (C₂₋₁₂)alkenyl; (C₂₋₁₂)alkynyl; (C₃₋₁₂)cycloalkyl; or(C₃₋₁₂)cycloalkenyl; where the alkyl, alkenyl, alkynyl, cycloalkyl andcycloalkenyl groups are optionally mono- or independentlyplurisubstituted with R¹², and where the alkyl, alkenyl, alkynylportions include linear or branched chains and may include cyclicportions.

In some embodiments of compounds of formula III, X is CH₂; the ringcontaining X is saturated; R¹, R² and R²⁵ are hydrogen; and R²⁴ isphenyl optionally mono- or independently plurisubstituted with R¹². Inother embodiments, X is CH₂; the ring containing X is saturated; R¹, R²and R²⁵ are hydrogen; and R²⁴ is R¹¹(CH₂)_(p)— where R¹¹ is2-oxopyrrolidinyl, (C₁₋₆)alkoxy, phenyl; phenoxy; (C₁₋₈)cycloalkyl;[3.3.3] bicyclic carbocyclic moiety; pyridinyl; naphthyl; cyclohexenyl;or adamantyl; where the 2-oxopyrrolidinyl, (C₁₋₆)alkoxy, phenyl,pyridinyl, and naphthyl groups are optionally mono- or independently di-or independently trisubstituted with R¹²; where the phenoxy group isoptionally mono- or independently disubstituted with (C₁₋₄)alkyl,(C₁₋₄)alkoxy, or halogen; and where the [3.3.3] bicyclic carbocyclicmoiety is optionally mono-or independently plurisubstituted with(C₁₋₈)alkyl; p is 0 to 3; and R¹² is halogen; trifluoromethyl; cyano;nitro; (C₁₋₆)alkyl; (C₁₋₆)alkoxy; cycloalkyl; carboxy; acetamido;hydroxy; hydroxy(C₁₋₆)alkyl; hydroxymethyl; trifluoromethoxy; sulfamoyl;carbamoyl; sulfonamido; alkylsufonyl; phenylsulfonyl; aryl; heteroaryl;where the aryl and heteroaryl groups are optionally mono- orindependently plurisubstituted with R⁷. In still other embodiments, X isCH₂; the ring containing X is saturated; R¹, R² and R²⁵ are hydrogen;and R²⁴ is (R¹³)₂CH(CH₂)_(q)—, where R¹³ is phenyl; in which the phenylgroups are independently optionally mono- or independently disubstitutedwith R¹²; and q is 0 to 3.

Compounds of formula III include those wherein X is CH₂; the ringcontaining X is saturated; R¹, R² and R²⁵ are hydrogen; and R²⁴ is agroup of the formula:

where R¹⁴ and R¹⁵ are independently hydrogen; (C₁₋₈)alkyl;(C₁₋₆)alkylcarbonyl; (C₃₋₁₂)cycloalkyl ring; (C₃₋₁₂)cycloalkenyl ring;benzyl; benzoyl; pyridine; pyrimidine; phenyl; phenylamino-carbonyl;alkylsulfonyl; or phenylsulfonyl; where the cycloalkyl ring isoptionally substituted with hydroxy(C₁₋₆)alkyl, and where the benzyl,benzoyl, pyridine, pyrimidine, phenyl, phenylaminocarbonyl,alkylsulfonyl, and phenylsulfonyl groups are optionally mono- orindependently di-substituted with R¹²; or R¹⁴ and R¹⁵ together form a(C₃₋₁₂)cycloalkyl ring; and s is 1 to 6.

Compounds of formula III also include those wherein X is CH₂; the ringcontaining X is saturated; R¹, R² and R²⁵ are hydrogen; and R²⁴ is agroup of the formula:

where R²¹ is hydrogen; (C₁₋₈)alkyl; benzyl; or phenyl; in which thebenzyl and phenyl groups are optionally mono- or independentlydi-substituted on the ring with R¹²; and t is 0 to 6.

In some embodiments of compounds of formula III, X is CH₂; the ringcontaining X is saturated; R¹, R² and R²⁴ are hydrogen. In otherembodiments, X is CH₂; the ring containing X is saturated; R¹, R², R²⁴are hydrogen; and R²⁵ is (C₁₋₁₂)alkyl; (C₂₋₁₂)alkenyl; (C₂₋₁₂)alkynyl;(C₃₋₁₂)cycloalkyl; or (C₃₋₁₂)cycloalkenyl; where the alkyl, alkenyl,alkynyl, cycloalkyl and cycloalkenyl groups are optionally mono- orindependently plurisubstituted with R¹², and where the alkyl, alkenyl,alkynyl portions include linear or branched chains and may includecyclic portions. In still other embodiments, X is CH₂; the ringcontaining X is saturated; R¹, R², R²⁴ are hydrogen; and R²⁵ is phenyloptionally mono- or independently plurisubstituted with R¹².

In some embodiments of compounds of formula III, X is CH₂; the ringcontaining X is saturated; R¹, R², R²⁴ are hydrogen; and R²⁵ isR″(CH₂)_(p)— where R¹¹ is 2-oxopyrrolidinyl, (C₁₋₆)alkoxy, phenyl;phenoxy; (C₁₋₈)cycloalkyl; [3.3.3] bicyclic carbocyclic moiety;pyridinyl; naphthyl; cyclohexenyl; or adamantyl; where the2-oxopyrrolidinyl, (C₁₋₆)alkoxy, phenyl, pyridinyl, and naphthyl groupsare optionally mono- or independently di- or independentlytrisubstituted with R¹²; where the phenoxy group is optionally mono- orindependently disubstituted with (C₁₋₄)alkyl, (C₁₋₄)alkoxy, or halogen;and where the [3.3.3] bicyclic carbocyclic moiety is optionally mono-orindependently plurisubstituted with (C₁₋₈)alkyl; p is 0 to 3; and R¹² ishalogen; trifluoromethyl; cyano; nitro; (C₁₋₆)alkyl; (C₁₋₆)alkoxy;cycloalkyl; carboxy; acetamido; hydroxy; hydroxy(C₁₋₆)alkyl;hydroxymethyl; trifluoromethoxy; sulfamoyl; carbamoyl; sulfonamido;alkylsufonyl; phenylsulfonyl; aryl; heteroaryl; where the aryl andheteroaryl groups are optionally mono- or independently plurisubstitutedwith R⁷.

In other embodiments of compounds of formula III, X is CH₂; the ringcontaining X is saturated; R¹, R², R²⁴ are hydrogen; and R²⁵ is(R¹³)₂CH(CH₂)_(q)—, where R¹³ is phenyl; in which the phenyl groups areindependently optionally mono- or independently disubstituted with R¹²;and q is 0 to 3. In still other embodiments, X is CH₂; the ringcontaining X is saturated; R¹, R², R²⁴ are hydrogen; and R²⁵ is a groupof the formula:

where R¹⁴ and R¹⁵ are independently hydrogen; (C₁₋₈)alkyl;(C₁₋₆)alkylcarbonyl; (C₃₋₁₂)cycloalkyl ring; (C₃₋₁₂)cycloalkenyl ring;benzyl; benzoyl; pyridine; pyrimidine; phenyl; phenylamino-carbonyl;alkylsulfonyl; or phenylsulfonyl; where the cycloalkyl ring isoptionally substituted with hydroxy(C₁₋₆)alkyl, and where the benzyl,benzoyl, pyridine, pyrimidine, phenyl, phenylaminocarbonyl,alkylsulfonyl, and phenylsulfonyl groups are optionally mono- orindependently di-substituted with R¹²; or R¹⁴ and R¹⁵ together form a(C₃₋₁₂)cycloalkyl ring; and t is 0 to 6.

In certain embodiments of compounds of formula III, X is CH₂; the ringcontaining X is saturated; R¹, R², R²⁴ are hydrogen; and R²⁵ is a groupof the formula:

where R²¹ is hydrogen; (C₁₋₈)alkyl; benzyl; or phenyl; in which thebenzyl and phenyl groups are optionally mono- or independentlydi-substituted on the ring with R¹²; and t is 0 to 6.

In some embodiments of compounds of formula III, X is CH₂; the ringcontaining X is saturated; R¹, R², R²⁴ and R²⁶ are hydrogen. In otherembodiments, X is CH₂; the ring containing X is saturated; R¹, R², R²⁴are hydrogen; and R²⁶ is (C₁₋₁₂)alkyl; (C₂₋₁₂)alkenyl; (C₂₋₁₂)alkynyl;(C₃₋₁₂)cycloalkyl; or (C₃₋₁₂)cycloalkenyl; where the alkyl, alkenyl,alkynyl, cycloalkyl and cycloalkenyl groups are optionally mono- orindependently plurisubstituted with R¹², and where the alkyl, alkenyl,alkynyl portions include linear or branched chains and may includecyclic portions. In yet other embodiments, X is CH₂; the ring containingX is saturated; R¹, R², R²⁴ are hydrogen; and R²⁶ is phenyl optionallymono- or independently plurisubstituted with R¹².

Compounds of formula III include those wherein X is CH₂; the ringcontaining X is saturated; R¹, R², R²⁴ are hydrogen; and R²⁶ isR²⁷(CH₂)_(p)—, where R²⁷ is 2-oxopyrrolidinyl; (C₁₋₆)alkoxy; phenyl;phenoxy; (C₁₋₈)cycloalkyl; [3.3.3] bicyclic carbocyclic moiety;pyridinyl; naphthyl; cyclohexenyl; (C₁₋₈)alkylcarbonyl;(C₃₋₁₂)cycloalkylcarbonyl; benzyl; benzoyl; pyrimidinyl;phenylaminocarbonyl; alkylsulfonyl; phenylsulfonyl; or adamantyl; wherethe cycloalkyl ring is optionally substituted with hydroxy(C₁₋₆)alkyl;where the 2-oxopyrrolidinyl, (C₁₋₆)alkoxy, phenyl, pyridinyl, benzyl,benzoyl, pyrimidinyl, phenylaminocarbonyl, alkylsulfonyl,phenylsulfonyl, and naphthyl groups are optionally mono- orindependently di- or independently trisubstituted with R¹²; where thephenoxy group is optionally mono- or independently disubstituted with(C₁₋₄)alkyl, (C₁₋₄)alkoxy, or halogen; and where the [3.3.3] bicycliccarbocyclic moiety is optionally mono-or independently plurisubstitutedwith (C₁₋₈)alkyl; p is 0 to 3; and R¹² is halogen; trifluoromethyl;cyano; nitro; (C₁₋₆)alkyl; (C₁₋₆)alkoxy; cycloalkyl; carboxy; acetamido;hydroxy; hydroxy(C₁₋₆)alkyl; hydroxymethyl; trifluoromethoxy; sulfamoyl;carbamoyl; sulfonamido; alkylsufonyl; phenylsulfonyl; aryl; heteroaryl;where the aryl and heteroaryl groups are optionally mono- orindependently plurisubstituted with R⁷; and p is 0 to 3. In someembodiments of compounds of formula III, X is CH₂; the ring containing Xis saturated; R¹, R², R²⁴ are hydrogen; and R²⁶ is (R¹³)₂CH(CH₂)_(q)—;where R¹³ is phenyl, in which the phenyl groups are independentlyoptionally mono- or independently disubstituted with R¹²; and q is 0 to3.

Compounds of formula III include those wherein X is CH₂; the ringcontaining X is saturated; R¹, R², R²⁴ are hydrogen; and R²⁶ is a groupof the formula:

where R¹⁴ and R¹⁵ are independently hydrogen; (C₁₋₈)alkyl;(C₁₋₆)alkylcarbonyl; (C₃₋₁₂)cycloalkyl ring; (C₃₋₁₂)cycloalkenyl ring;benzyl; benzoyl; pyridine; pyrimidine; phenyl; phenylamino-carbonyl;alkylsulfonyl; or phenylsulfonyl; where the cycloalkyl ring isoptionally substituted with hydroxy(C₁₋₆)alkyl, and where the benzyl,benzoyl, pyridine, pyrimidine, phenyl, phenylaminocarbonyl,alkylsulfonyl, and phenylsulfonyl groups are optionally mono- orindependently di-substituted with R¹²; or R¹⁴ and R¹⁵ together form a(C₃₋₁₂)cycloalkyl ring; and r is 0 or 2 to 6.

Compounds of formula III also include those wherein X is CH₂; the ringcontaining X is saturated; R¹, R², R²⁴ are hydrogen; and R²⁶ is a groupof the formula:

where R²¹ is hydrogen; (C₁₋₈)alkyl; benzyl; or phenyl; in which thebenzyl and phenyl groups are optionally mono- or independentlydi-substituted on the ring with R¹²; and t is 0 or 2 to 6.

In some embodiments of compounds of formula I, CR^(i)R^(ii) is present.In other embodiments of compounds of formula I where CR^(i)R^(ii) ispresent, the compound has formula IVA or IVB:

wherein

R is

a) hydrogen;

b) (C₁₋₁₂)alkyl; (C₂₋₁₂)alkenyl; (C₂₋₁₂)alkynyl; (C₃₋₁₂)cycloalkyl; or(C₃₋₁₂)cycloalkenyl; where the alkyl, alkenyl, alkynyl, cycloalkyl andcycloalkenyl groups are optionally mono- or independentlyplurisubstituted with R¹², and where the alkyl, alkenyl, alkynylportions include linear or branched chains and may include cyclicportions;

c) aryl; or heteroaryl; where the aryl and heteroaryl groups areoptionally mono- or independently plurisubstituted with R¹²;

d) R¹¹(CH₂)_(p)— where R¹¹ is 2-oxopyrrolidinyl; (C₁₋₆)alkoxy; phenyl;phenoxy; (C₁₋₈)cycloalkyl; [3.3.3] bicyclic carbocyclic moiety;pyridinyl; naphthyl; cyclohexenyl; or adamantyl; where the2-oxopyrrolidinyl, (C₁₋₆)alkoxy, phenyl, pyridinyl, and naphthyl groupsare optionally mono- or independently di- or independentlytrisubstituted with R¹²; where the phenoxy group is optionally mono- orindependently disubstituted with (C₁₋₄)alkyl, (C₁₋₄)alkoxy, or halogen;and where the [3.3.3] bicyclic carbocyclic moiety is optionally mono-orindependently plurisubstituted with (C₁₋₈)alkyl; p is 0 to 3; and

R¹² is halogen; trifluoromethyl; cyano; nitro; (C₁₋₆)alkyl;(C₁₋₆)alkoxy; cycloalkyl; carboxy; acetamido; hydroxy;hydroxy(C₁₋₆)alkyl; hydroxymethyl; trifluoromethoxy; sulfamoyl;carbamoyl; sulfonamido; alkylsufonyl; phenylsulfonyl; aryl; heteroaryl;where the aryl and heteroaryl groups are optionally mono- orindependently plurisubstituted with R⁷;

e) (R¹³)₂CH(CH₂)_(q)—, where R¹³ is phenyl; in which the phenyl groupsare independently optionally mono- or independently disubstituted withR¹²; and q is 0 to 3;

f) a group of the formula:

where R¹⁴ and R¹⁵ are independently hydrogen; (C₁₋₈)alkyl;(C₁₋₆)alkylcarbonyl; (C₃₋₁₂)cycloalkyl ring; (C₃₋₁₂)cycloalkenyl ring;benzyl; benzoyl; pyridine; pyrimidine; phenyl; phenylamino-carbonyl;alkylsulfonyl; or phenylsulfonyl; where the cycloalkyl ring isoptionally substituted with hydroxy(C₁₋₆)alkyl, and where the benzyl,benzoyl, pyridine, pyrimidine, phenyl, phenylaminocarbonyl,alkylsulfonyl, and phenylsulfonyl groups are optionally mono- orindependently di-substituted with R¹²; or R¹⁴ and R¹⁵ together form a(C₃₋₁₂)cycloalkyl ring; and s is 0 to 6; or

g) a group of the formula:

where R²¹ is hydrogen; (C₁₋₈)alkyl; benzyl; or phenyl; in which thebenzyl and phenyl groups are optionally mono- or independentlydi-substituted on the ring with R¹²; and t is 0 to 6;

It has further been discovered that certain boronic acid compounds ofthe invention can exist as either linear or cyclic isomers. Typically,such compounds form an equilibrium mixture in aqueous solution. As shownin FIG. 1, the concentration of the two isomers of such compounds istypically pH dependent. Thus, it is expected that such inventivecompounds will exist as a mixture of linear and cyclic isomers in vivo.Moreover, the cyclic forms of inventive compounds may serve as novel,orally available prodrugs. Hence, in this aspect of the invention, thereare provided compounds that have the formula VA, VB, or a mixturethereof:

including all enantiomers, diastereoisomers, solvates, hydrates andpharmaceutically acceptable salts thereof, wherein:

n is 1 to 3;

X is CH₂; S; O; CF₂ or C(CH₃)₂;

Z is H; halogen; hydroxyl; (C₁₋₆)alkoxy; (C₁₋₁₂)alkyl;(C₃₋₁₂)cycloalkyl; phenyl; or heteroaryl; where the phenyl andheteroaryl groups are optionally mono- or independently plurisubstitutedwith R⁷;

optionally, X together with an adjacent ring carbon and Z form a fusedcyclopropyl; and

optionally, one of the bonds in the ring containing X is a double bond;

R¹ and R² independently or together are hydrogen; a boronic acidprotecting group; or a group capable of being hydrolyzed to a hydroxylgroup in an aqueous solution at physiological pH or in biologicalfluids;

R³, R⁴ and R⁵ are selected from (dd) or (ee):

-   -   (dd) R³ and R⁴ are hydrogen; and        -   R⁵ is            -   a) hydrogen, provided that R⁵ is not hydrogen when n is                1, X is CH₂, and Z is H;            -   b) (C₁₋₁₂)alkyl; (C₂₋₁₂)alkenyl; (C₂₋₁₂)alkynyl; (C₃₋₁₂)                cycloalkyl; or (C₃₋₁₂)cycloalkenyl; where the alkyl,                alkenyl, alkynyl, cycloalkyl and cycloalkenyl groups are                optionally mono- or independently plurisubstituted with                R⁶, and where the alkyl, alkenyl, alkynyl portions                include linear or branched chains and may include cyclic                portions;            -   R⁶ is (C₁₋₆)alkyl; (C₁₋₆)alkoxy; cycloalkyl; carboxy;                acetamido; cyano; nitro; halogen; hydroxy;                hydroxy(C₁₋₆)alkyl; hydroxymethyl; trifluoromethyl;                trifluoromethoxy; sulfamoyl; sulfonamido; carbamoyl;                aryl; heteroaryl; where the aryl and heteroaryl groups                are optionally mono- or independently plurisubstituted                with R⁷; amino, where the amino group is optionally                mono- or independently plurisubstituted with R⁸; —SOR⁸;                —SO₂R⁸; —COR⁸; —CO₂R⁸, —CONHR⁸; —CON(R⁸)₂; —OR⁸; or                —S—R⁸;

R⁷ is halogen; (C₁₋₁₀)alkyl; (C₁₋₁₀)alkoxy; (C₁₋₁₀)alkylamino;(C₁₋₁₀)dialkylamino; benzyl; benzyloxy; hydroxyl(C₁₋₆)alkyl;hydroxymethyl; nitro; trifluoromethyl; trifluoromethoxy;trifluoromethylthio; N-hydroxyimino; cyano; carboxy; acetamido; hydroxy;sulfamoyl; sulfonamido; or carbamoyl;

-   -   -   -   R⁸ is (C₁₋₁₀)alkyl; (C₂₋₁₀)alkenyl; (C₂₋₁₀)alkynyl;                (C₃₋₁₀)cycloalkyl; (C₅₋₁₀)cycloalkenyl; benzyl;                phenethyl; aryl; or heteroaryl; where the alkyl,                alkenyl, alkynyl, cycloalkyl, cycloalkenyl groups are                optionally mono- or independently plurisubstituted with                aryl or heteroaryl where the aryl and heteroaryl groups                are optionally mono- or independently plurisubstituted                with R⁷; and where the aryl and heteroaryl groups are                optionally mono- or independently plurisubstituted with                R⁷;            -   c) aryl optionally fused to a (C₃₋₁₀)cycloalkyl; or                heteroaryl optionally fused to a (C₃₋₁₀)cycloalkyl;                where the aryl and heteroaryl groups are optionally                mono- or independently plurisubstituted with R⁷;            -   d) indanyl; 1,2,3,4-tetrahydronaphthyl;                (CH₂)_(j)adamantyl in which j is 0-3; or a [2.2.1] or                [3.1.1] bicyclic carbocyclic moiety, including                (4-pentylbicyclo[2.2.2]oct-1-yl)amine; where the                indanyl, 1,2,3,4-tetrahydronaphthyl, (CH₂)_(j)                adamantyl, and [2.2.1] or [3.1.1] bicyclic carbocyclic                moieties are optionally mono- or independently                plurisubstituted with hydroxy, (C₁₋₈)alkyl,                (C₁₋₈)alkoxy, (C₁₋₈)alkanoyloxy, or R⁹R¹⁰N—CO—O—, where                R⁹ and R¹⁰ are independently (C₁₋₈)alkyl, or phenyl,                where the alkyl and phenyl groups are optionally mono-                or independently plurisubstituted with (C₁₋₈)alkyl,                (C₁₋₈)alkoxy, halogen, or trifluoromethyl, or R⁹ and R¹⁰                together are (C₃₋₆)alkylene;            -   e) R¹¹(CH₂)_(p)— where R¹¹ is 2-oxopyrrolidinyl;                (C₁₋₆)alkoxy; phenyl; phenoxy; (C₁₋₈)cycloalkyl; [3.3.3]                bicyclic carbocyclic moiety; pyridinyl; naphthyl;                cyclohexenyl; or adamantyl; where the 2-oxopyrrolidinyl,                (C₁₋₆)alkoxy, phenyl, pyridinyl, and naphthyl groups are                optionally mono- or independently di- or independently                trisubstituted with R¹²; where the phenoxy group is                optionally mono- or independently disubstituted with                (C₁₋₄)alkyl, (C₁₋₄)alkoxy, or halogen; and where the                [3.3.3] bicyclic carbocyclic moiety is optionally                mono-or independently plurisubstituted with (C₁₋₈)alkyl;                and p is 0 to 3;            -   R¹² is halogen; trifluoromethyl; cyano; nitro;                (C₁₋₆)alkyl; (C₁₋₆)alkoxy; cycloalkyl; carboxy;                acetamido; hydroxy; hydroxy(C₁₋₆)alkyl; hydroxymethyl;                trifluoromethoxy; sulfamoyl; carbamoyl; sulfonamido;                alkylsufonyl; phenylsulfonyl; aryl; heteroaryl; where                the aryl and heteroaryl groups are optionally mono- or                independently plurisubstituted with R⁷;

f) (R¹³)₂CH(CH₂)_(q)—, where R¹³ is phenyl; in which the phenyl groupsare independently optionally mono- or independently disubstituted withR¹²; and q is 0 to 3;

-   -   -   -   g) a group of the formula:

where R¹⁴ and R¹⁵ are independently hydrogen; (C₁₋₈)alkyl;(C₁₋₆)alkylcarbonyl; (C₃₋₁₂)cycloalkyl ring; (C₃₋₁₂)cycloalkenyl ring;benzyl; benzoyl; pyridine; pyrimidine; phenyl; phenylamino-carbonyl;alkylsulfonyl; or phenylsulfonyl; where the cycloalkyl ring isoptionally substituted with hydroxy(C₁₋₆)alkyl, and where the benzyl,benzoyl, pyridine, pyrimidine, phenyl, phenylaminocarbonyl,alkylsulfonyl, and phenylsulfonyl groups are optionally mono- orindependently di-substituted with R¹²; or R¹⁴ and R¹⁵ together form a(C₃₋₁₂)cycloalkyl ring; and r is 2 to 6;

-   -   -   -   h) a group of the formula:

where R¹⁶ and R¹⁷ are each independently hydrogen; (C₁₋₈)alkyl;(C₁₋₆)alkylcarbonyl; di-(C₁₋₆)alkylaminocarbonyl; benzyl; benzoyl;pyridine; pyrimidine; phenyl; phenylaminocarbonyl; alkylsulfonyl; orphenylsulfonyl; where the benzyl, benzoyl, pyridine, pyrimidine, phenyl,phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups areoptionally mono- or independently di-substituted with R¹²; or R¹⁶ andR¹⁷ together form a (C₃₋₁₂)cycloalkyl ring; and s is 1 to 6;

-   -   -   -   i) a group of the formula:

where R¹⁸ and R¹⁹ are independently hydrogen; (C₁₋₈)alkyl;(C₁₋₆)alkylcarbonyl; di-(C₁₋₆)alkylaminocarbonyl; benzyl; benzothiazole;benzoyl; pyridine; pyrimidine; phenyl; phenylaminocarbonyl;alkylsulfonyl; or phenylsulfonyl; where the benzyl, benzoyl,benzothiazole, pyridine, pyrimidine, phenyl, phenylaminocarbonyl,alkylsulfonyl, and phenylsulfonyl groups are optionally mono- orindependently di-substituted with R¹²; or R¹⁸ and R¹⁹ together form a(C₃₋₁₂)cycloalkyl ring; each t is independently 0 to 6; and u is 0 to 3;

-   -   -   -   j) a group of the formula:

(phenyl-CH₂—C(CH₃)₂—),

where the phenyl group is optionally mono- or independentlyplurisubstituted with R¹²;

-   -   -   -   k) a group of the formula:

where R²⁰ is hydrogen; (C₁₋₈)alkyl; (C₁₋₆)alkylcarbonyl;di-(C₁₋₆)alkylaminocarbonyl; (C₃₋₈)cycloalkylcarbonyl; benzyl; benzoyl;(C₁₋₆)alkyloxycarbonyl; arlkyloxycarbonyl, pyridine; pyrimidine; phenyl;phenyl substituted thiazole ring; phenylaminocarbonyl; alkylsulfonyl; orphenylsulfonyl; where the benzyl, benzoyl, pyridine, pyrimidine, phenyl,phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups areoptionally mono- or independently di-substituted with R¹²; R_(x) ishydrogen; (C₁₋₈)alkyl; (C₃₋₁₂)cycloalkyl; benzyl; phenyl; where thebenzyl and phenyl, groups are optionally mono- or independentlydi-substituted on the ring with R¹²; R_(y) is absent or is halogen,(C₁₋₈)alkyl, (C₁₋₈)alkoxy, O-alkylcarboxylate, O-aralkylcarboxylate,N-alkylcarboxamido, N-aralkylcarboxamido; or phenyl; s is 1 to 6; t is 0to 6; and u is 0 to 3; or

-   -   -   -   l) a group of the formula:

where R²¹ is hydrogen; (C₁₋₈)alkyl; benzyl; or phenyl; in which thebenzyl and phenyl groups are optionally mono- or independentlydi-substituted on the ring with R¹²; each t is independently 0 to 6; andu is 0 to 3; or

-   -   (ee) R³, R⁴ and R⁵ are independently hydrogen; alkyl; alkenyl;        alkynyl; cycloalkyl; cycloalkylalkyl; bicycloalkyl;        tricycloalkyl; alkylcycloalkyl; hydroxyalkyl;        hydroxyalkylcycloalkyl; hydroxycycloalkyl; hydroxybicycloalkyl;        hydroxytricycloalkyl; bicycloalkylalkyl; alkylbicycloalkyl;        alkylthioalkyl; arylalkylthioalkyl; cycloalkenyl; aryl, aralkyl;        heteroaryl; heteroarylalkyl; cycloheteroalkyl or        cycloheteroalkylalkyl; all optionally mono- or independently        plurisubstituted with halogen, alkyl, polyhaloalkyl, alkoxy,        haloalkoxy, polyhaloalkoxy, alkoxycarbonyl, alkenyl, alkynyl,        cycloalkyl, cycloalkylalkyl, polycycloalkyl, heteroarylamino,        arylamino, cycloheteroalkyl, cycloheteroalkylalkyl, hydroxy,        hydroxyalkyl, nitro, cyano, amino, substituted amino,        alkylamino, dialkylamino, thiol, alkylthio, alkylcarbonyl, acyl,        alkoxycarbonyl, aminocarbonyl, alkynylaminocarbonyl,        alkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyloxy,        alkylcarbonylamino, arylcarbonylamino, alkylsulfonylamino,        alkylaminocarbonyl-amino, alkoxycarbonylamino, alkylsulfonyl,        aminosulfinyl, aminosulfonyl, alkylsulfinyl, sulfonamido or        sulfonyl; provided that when n is 1, X is CH₂, the ring        containing X is saturated, and Z, R³ and R⁵ are H, R⁴ is not a        side chain of a naturally occurring α-amino acid; and provided        that when n is 1, X is CH₂, the ring containing X is saturated,        and Z and R⁵ are H, R³ and R⁴ are not both methyl; and

wherein the bond containing the wavy line signifies the point ofattachment.

In some embodiments of compounds of formula VA and VB, R¹ and R²independently or together are the boronic acid protecting group formedfrom (+)-pinanediol; pinacol; 1,2-dicyclohexyl-ethanediol;1,2-ethanediol; 2,2-diethanolamine; 1,3-propanediol; 2,3-butanediol,diisopropyl tartrate; 1,4-butanediol; diisopropylethanediol;(S,S,)-5,6-decanediol; 1,1,2-triphenyl-1,2-ethanediol;(2R,3R)-1,4-dimethyoxy-1,1,4,4-tetraphenyl-2,3-butanediol; methanol;ethanol; isopropanol; catechol; or 1-butanol. In other embodiments, R¹and R² independently or together are a group capable of being hydrolyzedto a hydroxyl group in an aqueous solution at physiological pH or inbiological fluids formed from 1,2-dicyclohexylethanediol;1,2-ethanediol; 1,3-propanediol; 2,3-butanediol, 1,4-butanediol;diisopropylethanediol; methanol; ethanol; isopropanol; or 1-butanol.

In some embodiments of compounds of formula VA or VB,

-   -   R³ and R⁴ are independently hydrogen, alkyl; alkenyl; alkynyl;        cycloalkyl; cycloalkylalkyl; bicycloalkyl; tricycloalkyl;        alkylcycloalkyl; hydroxyalkyl; hydroxyalkylcycloalkyl;        hydroxycycloalkyl; hydroxybicycloalkyl; hydroxytricycloalkyl;        bicycloalkylalkyl; alkylbicycloalkyl; alkylthioalkyl;        arylalkylthioalkyl; cycloalkenyl; aryl, aralkyl; heteroaryl;        heteroarylalkyl; cycloheteroalkyl or cycloheteroalkylalkyl; all        optionally mono- or independently plurisubstituted with halogen,        alkyl, polyhaloalkyl, alkoxy, haloalkoxy, polyhaloalkoxy,        alkoxycarbonyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl,        polycycloalkyl, heteroarylamino, arylamino, cycloheteroalkyl,        cycloheteroalkylalkyl, hydroxy, hydroxyalkyl, nitro, cyano,        amino, substituted amino, alkylamino, dialkylamino, thiol,        alkylthio, alkylcarbonyl, acyl, alkoxycarbonyl, aminocarbonyl,        alkynylaminocarbonyl, alkylaminocarbonyl, alkenylaminocarbonyl,        alkylcarbonyloxy, alkylcarbonylamino, arylcarbonylamino,        alkylsulfonylamino, alkylaminocarbonyl-amino,        alkoxycarbonylamino, alkylsulfonyl, aminosulfinyl,        aminosulfonyl, alkylsulfinyl, sulfonamido or sulfonyl; and    -   R⁵ is alkyl; alkenyl; alkynyl; cycloalkyl; cycloalkylalkyl;        bicycloalkyl; tricycloalkyl; alkylcycloalkyl; hydroxyalkyl;        hydroxyalkylcycloalkyl; hydroxycycloalkyl; hydroxybicycloalkyl;        hydroxytricycloalkyl; bicycloalkylalkyl; alkylbicycloalkyl;        alkylthioalkyl; arylalkylthioalkyl; cycloalkenyl; aryl, aralkyl;        heteroaryl; heteroarylalkyl; cycloheteroalkyl or        cycloheteroalkylalkyl; all optionally mono- or independently        plurisubstituted with halogen, alkyl, polyhaloalkyl, alkoxy,        haloalkoxy, polyhaloalkoxy, alkoxycarbonyl, alkenyl, alkynyl,        cycloalkyl, cycloalkylalkyl, polycycloalkyl, heteroarylamino,        arylamino, cycloheteroalkyl, cycloheteroalkylalkyl, hydroxy,        hydroxyalkyl, nitro, cyano, amino, substituted amino,        alkylamino, dialkylamino, thiol, alkylthio, alkylcarbonyl, acyl,        alkoxycarbonyl, aminocarbonyl, alkynylamino-carbonyl,        alkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyloxy,        alkylcarbonylamino, arylcarbonylamino, alkylsulfonylamino,        alkylaminocarbonyl-amino, alkoxycarbonylamino, alkylsulfonyl,        aminosulfinyl, aminosulfonyl, alkylsulfinyl, sulfonamido or        sulfonyl.

In still other embodiments of compounds of formula VA or VB, X is CH₂;the ring containing X is saturated; R¹, R², R³ and R⁴ are hydrogen; andR⁵ is (C₁₋₁₂)alkyl; (C₂₋₁₂)alkenyl; (C₂₋₁₂)alkynyl; (C₃₋₁₂)cycloalkyl;or (C₃₋₁₂)cycloalkenyl; where the alkyl, alkenyl, alkynyl, cycloalkyland cycloalkenyl groups are optionally mono- or independentlyplurisubstituted with R⁶, and where the alkyl, alkenyl, alkynyl portionsinclude linear or branched chains and may include cyclic portions. Insome such embodiments, R⁵ is (C₃₋₁₂) cycloalkyl such as cyclopentyl.

In some embodiments of compounds of formula VA or VB, X is CH₂; the ringcontaining X is saturated; R¹, R², R³ and R⁴ are hydrogen; and R⁵ isindanyl; 1,2,3,4-tetrahydronaphthyl; (CH₂)_(j) adamantyl in which j is0-3; or a [2.2.1] or [3.1.1] bicyclic carbocyclic moiety, including(4-pentylbicyclo[2.2.2]-oct-1-yl)amine; where the indanyl,1,2,3,4-tetrahydronaphthyl, (CH₂)_(j) adamantyl, and [2.2.1] or [3.1.1]bicyclic carbocyclic moieties are optionally mono- or independentlyplurisubstituted with hydroxy, (C₁₋₈)alkyl, (C₁₋₈)alkoxy,(C₁₋₈)alkanoyloxy, or R⁹R¹⁰N—CO—O—, where R⁹ and R¹⁰ are independently(C₁₋₈)alkyl, or phenyl, where the alkyl and phenyl groups are optionallymono- or independently plurisubstituted with (C₁₋₈)alkyl, (C₁₋₈)alkoxy,halogen, or trifluoromethyl, or R⁹ and R¹⁰ together are (C₃₋₆)alkylene.

Compounds of formula VA or VB include those wherein X is CH₂; the ringcontaining X is saturated; R¹, R², R³ and R⁴ are hydrogen; and R⁵ isR¹¹(CH₂)_(p)— where R¹¹ is 2-oxopyrrolidinyl; (C₁₋₆)alkoxy; phenyl;phenoxy; (C₁₋₈)cycloalkyl; [3.3.3] bicyclic carbocyclic moiety;pyridinyl; naphthyl; cyclohexenyl; or adamantyl; where the2-oxopyrrolidinyl, (C₁₋₆)alkoxy, phenyl, pyridinyl, and naphthyl groupsare optionally mono- or independently di- or independentlytrisubstituted with R¹²; where the phenoxy group is optionally mono- orindependently disubstituted with (C₁₋₄)alkyl, (C₁₋₄)alkoxy, or halogen;and where the [3.3.3] bicyclic carbocyclic moiety is optionally mono-orindependently plurisubstituted with (C₁₋₈)alkyl; p is 0 to 3; and R¹² ishalogen; trifluoromethyl; cyano; nitro; (C₁₋₆)alkyl; (C₁₋₆)alkoxy;cycloalkyl; carboxy; acetamido; hydroxy; hydroxy(C₁₋₆)alkyl;hydroxymethyl; trifluoromethoxy; sulfamoyl; carbamoyl; sulfonamido;alkylsufonyl; phenylsulfonyl; aryl; heteroaryl; where the aryl andheteroaryl groups are optionally mono- or independently plurisubstitutedwith R⁷.

Compounds of VA or VB further include those wherein X is CH₂; the ringcontaining X is saturated; R¹, R², R³ and R⁴ are hydrogen; and R⁵ is(R¹³)₂CH(CH₂)_(q)—, where R¹³ is phenyl; in which the phenyl groups areindependently optionally mono- or independently disubstituted with R¹²;and q is 0 to 3.

In some embodiments of compounds of formula VA or VB, X is CH₂; the ringcontaining X is saturated; R¹, R², R³ and R⁴ are hydrogen; and R⁵ is agroup of the formula:

where R¹⁴ and R¹⁵ are independently hydrogen; (C₁₋₈)alkyl;(C₁₋₆)alkylcarbonyl; (C₃₋₁₂)cycloalkyl ring; (C₃₋₁₂)cycloalkenyl ring;benzyl; benzoyl; pyridine; pyrimidine; phenyl; phenylamino-carbonyl;alkylsulfonyl; or phenylsulfonyl; where the cycloalkyl ring isoptionally substituted with hydroxy(C₁₋₆)alkyl, and where the benzyl,benzoyl, pyridine, pyrimidine, phenyl, phenylaminocarbonyl,alkylsulfonyl, and phenylsulfonyl groups are optionally mono- orindependently di-substituted with R¹²; or R¹⁴ and R¹⁵ together form a(C₃₋₁₂)cycloalkyl ring; and r is 2 to 6.

In other embodiments of compounds of formula VA or VB, X is CH₂; thering containing X is saturated; R¹, R², R³ and R⁴ are hydrogen; and R⁵is a group of the formula:

where R¹⁶ and R¹⁷ are each independently hydrogen; (C₁₋₈)alkyl;(C₁₋₆)alkylcarbonyl; di-(C₁₋₆)alkylaminocarbonyl; benzyl; benzoyl;pyridine; pyrimidine; phenyl; phenylaminocarbonyl; alkylsulfonyl; orphenylsulfonyl; where the benzyl, benzoyl, pyridine, pyrimidine, phenyl,phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups areoptionally mono- or independently di-substituted with R¹²; or R¹⁶ andR¹⁷ together form a (C₃₋₁₂)cycloalkyl ring; and s is 1 to 6.

In certain embodiments of compounds of formula VA or VB, X is CH₂; thering containing X is saturated; R¹, R², R³ and R⁴ are hydrogen; and R⁵is a group of the formula:

where R¹⁸ and R¹⁹ are independently hydrogen; (C₁₋₈)alkyl;(C₁₋₆)alkylcarbonyl; di-(C₁₋₆)alkylaminocarbonyl; benzyl; benzothiazole;benzoyl; pyridine; pyrimidine; phenyl; phenylaminocarbonyl;alkylsulfonyl; or phenylsulfonyl; where the benzyl, benzoyl,benzothiazole, pyridine, pyrimidine, phenyl, phenylaminocarbonyl,alkylsulfonyl, and phenylsulfonyl groups are optionally mono- orindependently di-substituted with R¹²; or R¹⁸ and R¹⁹ together form a(C₃₋₁₂)cycloalkyl ring; each t is independently 0 to 6; and u is 0 to 3.In some such embodiments, R⁵ has formula:

Compounds of formula VA or VB further include those wherein X is CH₂;the ring containing X is saturated; R¹, R², R³ and R⁴ are hydrogen; andR⁵ is a group of the formula:

(phenyl-CH₂—C(CH₃)₂—),

where the phenyl group is optionally mono- or independentlyplurisubstituted with R¹².

In some embodiments of compounds of formula VA or VB, X is CH₂; the ringcontaining X is saturated; R¹, R², R³ and R⁴ are hydrogen; and R⁵ is agroup of the formula:

where R²⁰ is hydrogen; (C₁₋₈)alkyl; (C₁₋₆)alkylcarbonyl;di-(C₁₋₆)alkylaminocarbonyl; (C₃₋₈)cycloalkylcarbonyl; benzyl; benzoyl;(C₁₋₆)alkyloxycarbonyl; arlkyloxycarbonyl, pyridine; pyrimidine; phenyl;phenyl substituted thiazole ring; phenylaminocarbonyl; alkylsulfonyl; orphenylsulfonyl; where the benzyl, benzoyl, pyridine, pyrimidine, phenyl,phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups areoptionally mono- or independently di-substituted with R¹²; R_(x) ishydrogen; (C₁₋₈)alkyl; (C₃₋₁₂)cycloalkyl; benzyl; phenyl; where thebenzyl and phenyl, groups are optionally mono- or independentlydi-substituted on the ring with R¹²; R_(y) is absent or is halogen,(C₁₋₈)alkyl, (C₁₋₈)alkoxy, O-alkylcarboxylate, O-aralkylcarboxylate,N-alkylcarboxamido, N-aralkylcarboxamido; or phenyl; s is 1 to 6; t is 0to 6; and u is 0 to 3; or

In some such embodiments, R⁵ has formula:

In other embodiments of compounds of formula VA or VB, X is CH₂; thering containing X is saturated; R¹, R², R³ and R⁴ are hydrogen; and R⁵is a group of the formula:

where R²¹ is hydrogen; (C₁₋₈)alkyl; benzyl; or phenyl; in which thebenzyl and phenyl groups are optionally mono- or independentlydi-substituted on the ring with R¹²; each t is independently 0 to 6; andu is 0 to 3. In some such embodiments, R⁵ has formula:

Compounds of formula VA or VB further include those wherein R¹ and R²are hydrogen; n is 1; X together with an adjacent ring carbon and Z forma fused cyclopropyl;

R³, R⁴ and R⁵ are independently hydrogen; alkyl; alkenyl; alkynyl;cycloalkyl; cycloalkylalkyl; bicycloalkyl; tricycloalkyl;alkylcycloalkyl; hydroxyalkyl; hydroxyalkylcycloalkyl;hydroxycycloalkyl; hydroxybicycloalkyl; hydroxytricycloalkyl;bicycloalkylalkyl; alkylbicycloalkyl; alkylthioalkyl;arylalkylthioalkyl; cycloalkenyl; aryl, aralkyl; heteroaryl;heteroarylalkyl; cycloheteroalkyl or cycloheteroalkylalkyl; alloptionally mono- or independently plurisubstituted with halogen, alkyl,polyhaloalkyl, alkoxy, haloalkoxy, polyhaloalkoxy, alkoxycarbonyl,alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, polycycloalkyl,heteroarylamino, arylamino, cycloheteroalkyl, cycloheteroalkylalkyl,hydroxy, hydroxyalkyl, nitro, cyano, amino, substituted amino,alkylamino, dialkylamino, thiol, alkylthio, alkylcarbonyl, acyl,alkoxycarbonyl, aminocarbonyl, alkynylaminocarbonyl, alkylaminocarbonyl,alkenylaminocarbonyl, alkylcarbonyloxy, alkylcarbonylamino,arylcarbonylamino, alkylsulfonylamino, alkylaminocarbonyl-amino,alkoxycarbonylamino, alkylsulfonyl, aminosulfinyl, aminosulfonyl,alkylsulfinyl, sulfonamido or sulfonyl.

In certain embodiments of compounds of formula VA or VB, thecompoundshave the formula:

or a mixture thereof.

Compounds of formula VA or VB include those having the formula:

or a mixture thereof.

In other embodiments, compounds of formula VA or VB include those havingthe formula:

or a mixture thereof; or the formula:

or a mixture thereof.

Compounds of formula VA or VB further include those having the formula:

or a mixture thereof.

In still other embodiments, compounds of formula VA or VB have theformula:

or a mixture thereof.

In yet other embodiments, compounds of formula VA or VB have theformula:

or a mixture thereof.

In still another aspect, the invention provides boronic acid inhibitorsof dipeptidyl peptidase-IV having an inhibition constant of 10micromolar or less for dipeptidyl peptidase-IV. Such inhibitorscomprises a boroproline (including boropyrrolidines, boropiperidines,and boroazepanes) attached to an amino acid through an amide bond. Theamino acid can be a beta-amino acid (including cyclic forms such as , anN-cycloalkyl-alpha-amino acid, an N-heterocyclyl-alpha amino acid, acyclic alpha-amino acid having at least one substituent on thealpha-amino acid ring or having a ring other than pyrrolidine, orN-substituted glycine. In some embodiments, the boronic acid inhibitoris of Formula I:

including all enantiomers, diastereoisomers, solvates, hydrates andpharmaceutically acceptable salts thereof, wherein:

n is 1 to 2;

X is CH₂; S; O; CF₂ or C(CH₃)₂;

Z is H; halogen; hydroxyl; (C₁₋₆)alkoxy; (C₁₋₁₂)alkyl;(C₃₋₁₂)cycloalkyl; phenyl; or heteroaryl; where the phenyl andheteroaryl groups are optionally mono- or independently plurisubstitutedwith R⁷;

optionally, X together with an adjacent ring carbon and Z form a fusedcyclopropyl; and

optionally, one of the bonds in the ring containing X is a double bond;

R¹ and R² independently or together are hydrogen; a boronic acidprotecting group; or a group capable of being hydrolyzed to a hydroxylgroup in an aqueous solution at physiological pH or in biologicalfluids;

CR^(i)R^(ii) may be present or absent, wherein if CR^(i)R^(ii) ispresent, then R^(i), R^(ii), R³, R⁴ and R⁵ are selected from (aa), (bb)or (cc):

-   -   (aa) R^(i), R^(ii), R³ and R⁴ are hydrogen; and        -   R⁵ is            -   a) hydrogen;            -   b) (C₁₋₁₂)alkyl; (C₂₋₁₂)alkenyl; (C₂₋₁₂)alkynyl;                (C₃₋₁₂)cycloalkyl; or (C₃₋₁₂)cycloalkenyl; where the                alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl                groups are optionally mono- or independently                plurisubstituted with R⁶, and where the alkyl, alkenyl,                alkynyl portions include linear or branched chains and                may include cyclic portions;            -   R⁶ is (C₁₋₆)alkyl; (C₁₋₆)alkoxy; cycloalkyl; carboxy;                acetamido; cyano; nitro; halogen; hydroxy;                hydroxy(C₁₋₆)alkyl; hydroxymethyl; trifluoromethyl;                trifluoromethoxy; sulfamoyl; sulfonamido; carbamoyl;                aryl; heteroaryl; where the aryl and heteroaryl groups                are optionally mono- or independently plurisubstituted                with R⁷; amino, where the amino group is optionally                mono- or independently plurisubstituted with R⁸;                —SOR^(B); —SO₂R⁸; —COR⁸; —CO₂R⁸, —CONHR⁸; —CON(R⁸)₂;                —OR⁸; or —S—R⁸;            -   R⁷ is halogen; (C₁₋₁₀)alkyl; (C₁₋₁₀)alkoxy;                (C₁₋₁₀)alkylamino; (C₁₋₁₀)dialkylamino; benzyl;                benzyloxy; hydroxyl(C₁₋₆)alkyl; hydroxymethyl; nitro;                trifluoromethyl; trifluoromethoxy; trifluoromethylthio;                N-hydroxyimino; cyano; carboxy; acetamido; hydroxy;                sulfamoyl; sulfonamido; or carbamoyl;            -   R⁸ is (C₁₋₁₀)alkyl; (C₂₋₁₀)alkenyl; (C₂₋₁₀)alkynyl;                (C₃₋₁₀)cycloalkyl; (C₅₋₁₀)cycloalkenyl; benzyl;                phenethyl; aryl; or heteroaryl; where the alkyl,                alkenyl, alkynyl, cycloalkyl, cycloalkenyl groups are                optionally mono- or independently plurisubstituted with                aryl or heteroaryl where the aryl and heteroaryl groups                are optionally mono- or independently plurisubstituted                with R⁷; and where the aryl and heteroaryl groups are                optionally mono- or independently plurisubstituted with                R⁷;            -   c) aryl optionally fused to a (C₃₋₁₀)cycloalkyl; or                heteroaryl optionally fused to a (C₃₋₁₀)cycloalkyl;                where the aryl and heteroaryl groups are optionally                mono- or independently plurisubstituted with R⁷;            -   d) indanyl; 1,2,3,4-tetrahydronaphthyl;                (CH₂)_(j)adamantyl in which j is 0-3; or a [2.2.1] or                [3.1.1] bicyclic carbocyclic moiety, including                (4-pentylbicyclo[2.2.2]oct-1-yl)amine; where the                indanyl, 1,2,3,4-tetrahydronaphthyl, (CH₂)_(j)                adamantyl, and [2.2.1] or [3.1.1] bicyclic carbocyclic                moieties are optionally mono- or independently                plurisubstituted with hydroxy, (C₁₋₈)alkoxy,                (C₁₋₈)alkanoyloxy, or R⁹R¹⁰N—CO—O—, where R⁹ and R¹⁰ are                independently (C₁₋₈)alkyl, or phenyl, where the alkyl                and phenyl groups are optionally mono- or independently                plurisubstituted with (C₁₋₈)alkyl, (C₁₋₈)alkoxy,                halogen, or trifluoromethyl, or R⁹ and R¹⁰ together are                (C₃₋₆)alkylene;            -   e) R¹¹(CH2)_(p)— where R¹¹ is 2-oxopyrrolidinyl;                (C₁₋₆)alkoxy; phenyl; phenoxy; (C₁₋₈)cycloalkyl; [3.3.3]                bicyclic carbocyclic moiety; pyridinyl; naphthyl;                cyclohexenyl; or adamantyl; where the 2-oxopyrrolidinyl,                (C₁₋₆)alkoxy, phenyl, pyridinyl, and naphthyl groups are                optionally mono- or independently di- or independently                trisubstituted with R¹²; where the phenoxy group is                optionally mono- or independently disubstituted with                (C₁₋₄)alkyl, (C₁₋₄alkoxy, or halogen; and where the                [3.3.3] bicyclic carbocyclic moiety is optionally                mono-or independently plurisubstituted with (C₁₋₈)alkyl;                and p is 0 to 3;            -   R¹² is halogen; trifluoromethyl; cyano; nitro;                (C₁₋₆)alkyl; (C₁₋₆)alkoxy; cycloalkyl; carboxy;                acetamido; hydroxy; hydroxy(C₁₋₆)alkyl; hydroxymethyl;                trifluoromethoxy; sulfamoyl; carbamoyl; sulfonamido;                alkylsufonyl; phenylsulfonyl; aryl; heteroaryl; where                the aryl and heteroaryl groups are optionally mono- or                independently plurisubstituted with R⁷;            -   f) (R¹³)₂CH(CH₂)_(q)—, where R¹³ is phenyl; in which the                phenyl groups are independently optionally mono- or                independently disubstituted with R¹²; and q is 0 to 3;            -   g) a group of the formula:

where R¹⁴ and R¹⁵ are independently hydrogen; (C₁₋₈)alkyl;(C₁₋₆)alkylcarbonyl; (C₃₋₁₂)cycloalkyl ring; (C₃₋₁₂)cycloalkenyl ring;benzyl; benzoyl; pyridine; pyrimidine; phenyl; phenylamino-carbonyl;alkylsulfonyl; or phenylsulfonyl; where the cycloalkyl ring isoptionally substituted with hydroxy(C₁₋₆)alkyl, and where the benzyl,benzoyl, pyridine, pyrimidine, phenyl, phenylaminocarbonyl,alkylsulfonyl, and phenylsulfonyl groups are optionally mono- orindependently di-substituted with R¹²; or R¹⁴ and R¹⁵ together form a(C₃₋₁₂)cycloalkyl ring; and r is 2 to 6;

-   -   -   -   h) a group of the formula:

where R¹⁶ and R¹⁷ are each independently hydrogen; (C₁₋₈)alkyl;(C₁₋₆)alkylcarbonyl; di-(C₁₋₆)alkylaminocarbonyl; benzyl; benzoyl;pyridine; pyrimidine; phenyl; phenylaminocarbonyl; alkylsulfonyl; orphenylsulfonyl; where the benzyl, benzoyl, pyridine, pyrimidine, phenyl,phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups areoptionally mono- or independently di-substituted with R¹²; or R¹⁶ andR¹⁷ together form a (C₃₋₁₂)cycloalkyl ring; and s is 1 to 6;

-   -   -   -   i) a group of the formula:

where R¹⁸ and R¹⁹ are independently hydrogen; (C₁₋₈)alkyl;(C₁₋₆)alkylcarbonyl; di-(C₁₋₆)alkylaminocarbonyl; benzyl; benzothiazole;benzoyl; pyridine; pyrimidine; phenyl; phenylaminocarbonyl;alkylsulfonyl; or phenylsulfonyl; where the benzyl, benzoyl,benzothiazole, pyridine, pyrimidine, phenyl, phenylaminocarbonyl,alkylsulfonyl, and phenylsulfonyl groups are optionally mono- orindependently di-substituted with R¹²; or R¹⁸ and R¹⁹ together form a(C₃₋₁₂)cycloalkyl ring; each t is independently 0 to 6; and u is 0 to 3;

-   -   -   -   j) a group of the formula:

(phenyl-CH₂-C(CH₃) ₂-),

where the phenyl group is optionally mono- or independentlyplurisubstituted with R¹²;

-   -   -   -   k) a group f:

where R²⁰ is hydrogen; (C₁₋₈)alkyl; (C₁₋₆)alkylcarbonyl;di-(C₁₋₆)alkylaminocarbonyl; (C₃₋₈)cycloalkylcarbonyl; benzyl; benzoyl;(C₁₋₆)alkyloxycarbonyl; arlkyloxycarbonyl, pyridine; pyrimidine; phenyl;phenyl substituted thiazole ring; phenylaminocarbonyl; alkylsulfonyl; orphenylsulfonyl; where the benzyl, benzoyl, pyridine, pyrimidine, phenyl,phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups areoptionally mono- or independently di-substituted with R¹²; R_(x) ishydrogen; (C₁₋₈)alkyl; (C₃₋₁₂)cycloalkyl; benzyl; phenyl; where thebenzyl and phenyl, groups are optionally mono- or independentlydi-substituted on the ring with R¹²; R_(y) is absent or is halogen,(C₁₋₈)alkyl, (C₁₋₈)alkoxy, O-alkylcarboxylate, O-aralkylcarboxylate,N-alkylcarboxamido, N-aralkylcarboxamido; or phenyl; s is 1 to 6; t is 0to 6; and u is 0 to 3; or

-   -   -   -   l) a group of the formula:

where R²¹ is hydrogen; (C₁₋₈)alkyl; benzyl; or phenyl; in which thebenzyl and phenyl groups are optionally mono- or independentlydi-substituted on the ring with R¹²; each t is independently 0 to 6; andu is 0 to 3;

-   -   (bb) R^(i), R^(ii), R³, R⁴ and R⁵ are independently hydrogen;        alkyl; alkenyl; alkynyl; cycloalkyl; cycloalkylalkyl;        bicycloalkyl; tricycloalkyl; alkylcycloalkyl; hydroxyalkyl;        hydroxyalkylcycloalkyl; hydroxycycloalkyl; hydroxybicycloalkyl;        hydroxytricycloalkyl; bicycloalkylalkyl; alkylbicycloalkyl;        alkylthioalkyl; arylalkylthioalkyl; cycloalkenyl; aryl, aralkyl;        heteroaryl; heteroarylalkyl; cycloheteroalkyl or        cycloheteroalkylalkyl; all optionally mono- or independently        plurisubstituted with halogen, alkyl, polyhaloalkyl, alkoxy,        haloalkoxy, polyhaloalkoxy, alkoxycarbonyl, alkenyl, alkynyl,        cycloalkyl, cycloalkylalkyl, polycycloalkyl, heteroarylamino,        arylamino, cycloheteroalkyl, cycloheteroalkylalkyl, hydroxy,        hydroxyalkyl, nitro, cyano, amino, substituted amino,        alkylamino, dialkylamino, thiol, alkylthio, alkylcarbonyl, acyl,        alkoxycarbonyl, aminocarbonyl, alkynylamino-carbonyl,        alkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyloxy,        alkylcarbonylamino, arylcarbonylamino, alkylsulfonylamino,        alkylaminocarbonyl-amino, alkoxycarbonylamino, alkylsulfonyl,        aminosulfinyl, aminosulfonyl, alkylsulfinyl, sulfonamido or        sulfonyl; or        -   R^(i) together with R³ or R⁴, or R^(ii) together with R³ or            R⁴, and the atoms to which they are attached form a 4 to 8            membered cyclic, polycyclic or heterocyclic ring system            containing 1 to 3 heteroatoms selected from N, O, S, SO or            SO₂; and includes single rings, fused bicyclic and tricyclic            rings, which are optionally mono- or independently            plurisubstituted with any of the groups set forth in (aa);            or        -   R⁴ and R⁵ together form —(CR²²R²³)_(m)— where m is 2 to 6,            and R²² and R²³ are independently hydrogen; hydroxyl;            alkoxy; alkyl; alkenyl; alkynyl; cycloalkyl; halo; amino;            substituted amino; cycloalkylalkyl; cycloalkenyl; aryl;            arylalkyl; heteroaryl, heteroarylalkyl; cycloheteroalkyl;            cycloheteroalkylalkyl; alkylcarbonylamino;            arylcarbonylamino; alkoxycarbonyl-amino;            aryloxycarbonyl-amino; alkoxycarbonyl; aryloxycarbonyl; or            alkylaminocarbonylamino; or        -   R⁴ and R⁵ together with the atoms to which they are attached            form a 5 to 7 membered ring containing a total of 2 to 4            heteroatoms selected from N, O, S, SO, or SO₂; or        -   R⁴ and R⁵ together with the atoms to which they are attached            form a 4 to 8 membered cycloheteroalkyl ring wherein the            cycloheteroalkyl ring optionally has an aryl, heteroaryl or            3 to 7 membered cycloalkyl ring fused thereto; or    -   (cc) R^(i) and R³ are hydrogen; and R^(ii) and R⁴ together form        a 4 to 8 membered cyclic, polycyclic or heterocyclic ring system        containing 1 to 3 heteroatoms selected from N, O, S, SO and SO₂,        and includes single rings, fused bicyclic and tricyclic rings,        which are optionally mono- or independently plurisubstituted        with any of the groups set forth in (aa) or (bb) and        -   R⁵ is any of the groups in (aa) or (bb); and

if CR^(i)R^(ii) is absent, then R³, R⁴ and R⁵ are selected from (dd),(ee) or (ff):

-   -   (dd) R³ and R⁴ are hydrogen; and        -   R⁵ is            -   a) (C₁₋₁₂)alkyl; (C₂₋₁₂)alkenyl; (C₂₋₁₂)alkynyl;                (C₃₋₁₂)cycloalkyl; or (C₃₋₁₂)cycloalkenyl; where the                alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl                groups are optionally mono- or independently                plurisubstituted with R⁶, and where the alkyl, alkenyl,                alkynyl portions include linear or branched chains and                may include cyclic portions;            -   R⁶ is (C₁₋₆)alkyl; (C₁₋₆)alkoxy; cycloalkyl; carboxy;                acetamido; cyano; nitro; halogen; hydroxy;                hydroxy(C₁₋₆)alkyl; hydroxymethyl; trifluoromethyl;                trifluoromethoxy; sulfamoyl; sulfonamido; carbamoyl;                aryl; heteroaryl; where the aryl and heteroaryl groups                are optionally mono- or independently plurisubstituted                with R⁷; amino, where the amino group is optionally                mono- or independently plurisubstituted with R⁸; —SOR⁸;                —SO₂R⁸; —COR^(S); —CO₂R⁸, —CONHR⁸; —CON(R⁸)₂; —OR⁸; or                —S—R⁸;

R⁷ is halogen; (C₁₋₁₀)alkyl; (C₁₋₁₀)alkoxy; (C₁₋₁₀)alkylamino;(C₁₋₁₀)dialkylamino; benzyl; benzyloxy; hydroxyl(C₁₋₆)alkyl;hydroxymethyl; nitro; trifluoromethyl; trifluoromethoxy;trifluoromethylthio; N-hydroxyimino; cyano; carboxy; acetamido; hydroxy;sulfamoyl; sulfonamido; or carbamoyl;

R⁸ is (C₁₋₁₀)alkyl; (C₂₋₁₀)alkenyl; (C₂₋₁₀)alkynyl; (C₃₋₁₀)cycloalkyl;(C₅₋₁₀)cycloalkenyl; benzyl; phenethyl; aryl; or heteroaryl; where thealkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl groups are optionallymono- or independently plurisubstituted with aryl or heteroaryl wherethe aryl and heteroaryl groups are optionally mono- or independentlyplurisubstituted with R⁷; and where the aryl and heteroaryl groups areoptionally mono- or independently plurisubstituted with R⁷;

-   -   -   -   b) aryl optionally fused to a (C₃₋₁₀)cycloalkyl; or                heteroaryl optionally fused to a (C₃₋₁₀)cycloalkyl;                where the aryl and heteroaryl groups are optionally                mono- or independently plurisubstituted with R⁷;            -   c) indanyl; 1,2,3,4-tetrahydronaphthyl;                (CH₂)_(j)adamantyl in which j is 0-3; or a [2.2.1] or                [3.1.1] bicyclic carbocyclic moiety, including                (4-pentylbicyclo[2.2.2]oct-1-yl)amine; where the                indanyl, 1,2,3,4-tetrahydronaphthyl, (CH₂)_(j)                adamantyl, and [2.2.1] or [3.1.1] bicyclic carbocyclic                moieties are optionally mono- or independently                plurisubstituted with hydroxy, (C₁₋₈)alkyl,                (C₁₋₈)alkoxy, (C₁₋₈)alkanoyloxy, or R⁹R¹⁰N—CO—O—, where                R⁹ and R¹⁰ are independently (C₁₋₈)alkyl, or phenyl,                where the alkyl and phenyl groups are optionally mono-                or independently plurisubstituted with (C₁₋₈)alkyl,                (C₁₋₈)alkoxy, halogen, or trifluoromethyl, or R⁹ and R¹⁰                together are (C₃₋₆)alkylene;            -   d) R¹¹(CH₂)_(p)— where R¹¹ is 2-oxopyrrolidinyl;                (C₁₋₆)alkoxy; phenyl; phenoxy; (C₁₋₈)cycloalkyl; [3.3.3]                bicyclic carbocyclic moiety; pyridinyl; naphthyl;                cyclohexenyl; or adamantyl; where the 2-oxopyrrolidinyl,                (C₁₋₆)alkoxy, phenyl, pyridinyl, and naphthyl groups are                optionally mono- or independently di- or independently                trisubstituted with R¹²; where the phenoxy group is                optionally mono- or independently disubstituted with                (C₁₋₄)alkyl, (C₁₋₄)alkoxy, or halogen; and where the                [3.3.3] bicyclic carbocyclic moiety is optionally                mono-or independently plurisubstituted with (C₁₋₈)alkyl;                and p is 0 to 3;            -   R¹² is halogen; trifluoromethyl; cyano; nitro;                (C₁₋₆)alkyl; (C₁₋₆)alkoxy; cycloalkyl; carboxy;                acetamido; hydroxy; hydroxy(C₁₋₆)alkyl; hydroxymethyl;                trifluoromethoxy; sulfamoyl; carbamoyl; sulfonamido;                alkylsufonyl; phenylsulfonyl; aryl; heteroaryl; where                the aryl and heteroaryl groups are optionally mono- or                independently plurisubstituted with R⁷;            -   e) (R¹³)₂CH(CH₂)_(q)—, where R¹³ is phenyl; in which the                phenyl groups are independently optionally mono- or                independently disubstituted with R¹²; and q is 0 to 3;            -   f) a group of the formula:

where R¹⁴ and R¹⁵ are independently hydrogen; (C₁₋₈)alkyl;(C₁₋₆)alkylcarbonyl; (C₃₋₁₂)cycloalkyl ring; (C₃₋₁₂)cycloalkenyl ring;benzyl; benzoyl; pyridine; pyrimidine; phenyl; phenylamino-carbonyl;alkylsulfonyl; or phenylsulfonyl; where the cycloalkyl ring isoptionally substituted with hydroxy(C₁₋₆)alkyl, and where the benzyl,benzoyl, pyridine, pyrimidine, phenyl, phenylaminocarbonyl,alkylsulfonyl, and phenylsulfonyl groups are optionally mono- orindependently di-substituted with R¹²; or R¹⁴ and R¹⁵ together form a(C₃₋₁₂)cycloalkyl ring; and r is 2 to 6;

-   -   -   -   g) a group of the formula:

where R¹⁶ and R¹⁷ are each independently hydrogen; (C₁₋₈)alkyl;(C₁₋₆)alkylcarbonyl; di-(C₁₋₆)alkylaminocarbonyl; benzyl; benzoyl;pyridine; pyrimidine; phenyl; phenylaminocarbonyl; alkylsulfonyl; orphenylsulfonyl; where the benzyl, benzoyl, pyridine, pyrimidine, phenyl,phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups areoptionally mono- or independently di-substituted with R¹²; or R¹⁶ andR¹⁷ together form a (C₃₋₁₂)cycloalkyl ring; and s is 1 to 6;

-   -   -   -   h) a group of the formula:

where R¹⁸ and R¹⁹ are independently hydrogen; (C₁₋₈)alkyl;(C₁₋₆)alkylcarbonyl; di-(C₁₋₆)alkylaminocarbonyl; benzyl; benzothiazole;benzoyl; pyridine; pyrimidine; phenyl; phenylaminocarbonyl;alkylsulfonyl; or phenylsulfonyl; where the benzyl, benzoyl,benzothiazole, pyridine, pyrimidine, phenyl, phenylaminocarbonyl,alkylsulfonyl, and phenylsulfonyl groups are optionally mono- orindependently di-substituted with R¹²; or R¹⁸ and R¹⁹ together form a(C₃₋₁₂)cycloalkyl ring; each t is independently 0 to 6; and u is 0 to 3;

-   -   -   -   i) a group of the formula:

(phenyl-CH₂—C(CH₃)₂—),

where the phenyl group is optionally mono- or independentlyplurisubstituted with R¹²;

-   -   -   -   j) a group of the formula:

where R²⁰ is hydrogen; (C₁₋₈)alkyl; (C₁₋₆)alkylcarbonyl;di-(C₁₋₆)alkylaminocarbonyl; (C₃₋₈)cycloalkylcarbonyl; benzyl; benzoyl;(C₁₋₆)alkyloxycarbonyl; arlkyloxycarbonyl, pyridine; pyrimidine; phenyl;phenyl substituted thiazole ring; phenylaminocarbonyl; alkylsulfonyl; orphenylsulfonyl; where the benzyl, benzoyl, pyridine, pyrimidine, phenyl,phenylaminocarbonyl, alkylsulfonyl, and phenylsulfonyl groups areoptionally mono- or independently di-substituted with R¹²; R_(x) ishydrogen; (C₁₋₈)alkyl; (C₃₋₁₂)cycloalkyl; benzyl; phenyl; where thebenzyl and phenyl, groups are optionally mono- or independentlydi-substituted on the ring with R¹²; R_(y) is absent or is halogen,(C₁₋₈)alkyl, (C₁₋₈)alkoxy, O-alkylcarboxylate, O-aralkylcarboxylate,N-alkylcarboxamido, N-aralkylcarboxamido; or phenyl; s is 1 to 6; t is 0to 6; and u is 0 to 3; or

-   -   -   -   k) a group of the formula:

where R²¹ is hydrogen; (C₁₋₈)alkyl; benzyl; or phenyl; in which thebenzyl and phenyl groups are optionally mono- or independentlydi-substituted on the ring with R¹²; each t is independently 0 to 6; andu is 0 to 3; or

-   -   (ee) R³ and R⁴ are independently hydrogen, alkyl; alkenyl;        alkynyl; cycloalkyl; cycloalkylalkyl; bicycloalkyl;        tricycloalkyl; alkylcycloalkyl; hydroxyalkyl;        hydroxyalkylcycloalkyl; hydroxycycloalkyl; hydroxybicycloalkyl;        hydroxytricycloalkyl; bicycloalkylalkyl; alkylbicycloalkyl;        alkylthioalkyl; arylalkylthioalkyl; cycloalkenyl; aryl, aralkyl;        heteroaryl; heteroarylalkyl; cycloheteroalkyl or        cycloheteroalkylalkyl; all optionally mono- or independently        plurisubstituted with halogen, alkyl, polyhaloalkyl, alkoxy,        haloalkoxy, polyhaloalkoxy, alkoxycarbonyl, alkenyl, alkynyl,        cycloalkyl, cycloalkylalkyl, polycycloalkyl, heteroarylamino,        arylamino, cycloheteroalkyl, cycloheteroalkylalkyl, hydroxy,        hydroxyalkyl, nitro, cyano, amino, substituted amino,        alkylamino, dialkylamino, thiol, alkylthio, alkylcarbonyl, acyl,        alkoxycarbonyl, aminocarbonyl, alkynylaminocarbonyl,        alkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyloxy,        alkylcarbonylamino, arylcarbonylamino, alkylsulfonylamino,        alkylaminocarbonyl-amino, alkoxycarbonylamino, alkylsulfonyl,        aminosulfinyl, aminosulfonyl, alkylsulfinyl, sulfonamido or        sulfonyl;        -   R⁵ is alkyl; alkenyl; alkynyl; cycloalkyl; cycloalkylalkyl;            bicycloalkyl; tricycloalkyl; alkylcycloalkyl; hydroxyalkyl;            hydroxyalkylcycloalkyl; hydroxycycloalkyl;            hydroxybicycloalkyl; hydroxytricycloalkyl;            bicycloalkylalkyl; alkylbicycloalkyl; alkylthioalkyl;            arylalkylthioalkyl; cycloalkenyl; aryl, aralkyl; heteroaryl;            heteroarylalkyl; cycloheteroalkyl or cycloheteroalkylalkyl;            all optionally mono- or independently plurisubstituted with            halogen, alkyl, polyhaloalkyl, alkoxy, haloalkoxy,            polyhaloalkoxy, alkoxycarbonyl, alkenyl, alkynyl,            cycloalkyl, cycloalkylalkyl, polycycloalkyl,            heteroarylamino, arylamino, cycloheteroalkyl,            cycloheteroalkylalkyl, hydroxy, hydroxyalkyl, nitro, cyano,            amino, substituted amino, alkylamino, dialkylamino, thiol,            alkylthio, alkylcarbonyl, acyl, alkoxycarbonyl,            aminocarbonyl, alkynylaminocarbonyl, alkylaminocarbonyl,            alkenylaminocarbonyl, alkylcarbonyloxy, alkylcarbonylamino,            arylcarbonylamino, alkylsulfonylamino,            alkylaminocarbonyl-amino, alkoxycarbonylamino,            alkylsulfonyl, aminosulfinyl, aminosulfonyl, alkylsulfinyl,            sulfonamido or sulfonyl; or        -   R⁴ and R⁵ together form —(CR²²R²³)_(m)— wherein m is 2 to 6,            and R²² and R²³ are independently hydrogen; hydroxyl;            alkoxy; alkyl; alkenyl; alkynyl; cycloalkyl; halo; amino;            substituted amino; cycloalkylalkyl; cycloalkenyl; aryl;            arylalkyl; heteroaryl, heteroarylalkyl; cycloheteroalkyl;            cycloheteroalkylalkyl; alkylcarbonylamino;            arylcarbonylamino; alkoxycarbonyl-amino;            aryloxycarbonyl-amino; alkoxycarbonyl; aryloxycarbonyl; or            alkylaminocarbonylamino; provided that when n is 1, X is            CH₂, and Z and R³ are H, R⁴ and R⁵ together are not —(CH₂)₂—            or —(CH₂)₃—; or        -   R⁴ and R⁵ together with the atoms to which they are attached            form a 5 to 7 membered ring containing a total of 2 to 4            heteroatoms selected from N, O, S, SO, or SO₂; or        -   R⁴ and R⁵ together with the atoms to which they are attached            form a 4 to 8 membered cycloheteroalkyl ring wherein the            cycloheteroalkyl ring optionally has an aryl, heteroaryl or            3 to 7 membered cycloalkyl ring fused thereto; or    -   (ff) R³ is hydrogen; and R⁴ and R⁵ together with the atoms to        which they are attached form a 4 to 8 member mono- or polycyclic        heterocyclic ring system containing 1 to 3 heteroatoms selected        from N, O, S, SO and SO₂, wherein the heterocyclic ring system        is optionally mono- or independently plurisubstituted with any        of the groups set forth in (dd) or (ee); provided that when n is        1, X is CH₂, the ring containing X is saturated, and Z and R³        are H, R⁴ and R⁵ together are not —(CH₂)₂— or —(CH₂)₃—; and

wherein a bond containing a wavy line signifies a point of attachment.

The invention also relates to methods for preparing the above-describedcompounds. As shown below and as described in the EXAMPLES, thecompounds of formula I and II are prepared by reacting a cyclic amine(e.g., pyrrolidine or piperidine), suitably protected with a standardprotecting group such as Boc-, Fmoc-, CBz- or the like, withsec-BuLi/TMEDA followed by B(OCH₃)₃, to provide the methyl boronic esterderivative. Acid hydrolysis of the methyl esters with 2N HCl providesthe boronic acid intermediate 1. Reaction of 1 with (+) pinanediol,deprotection of the amino protecting group, and recrystallizationprovides the pinanediol ester 2 as an isomerically pure salt.

Intermediate 2 is useful for the synthesis of both series A and series Bcompounds. For example, N-acylation of 2 with chloroacetyl chlorideprovides the α-chloro amide 3. Treatment of 3 with Na₂CO₃ andcyclopentylamine, and hydrolysis of the pinanediol boronic ester,provides a compound of formula I, 4. Alternatively, coupling ofintermediate 2 with N-Boc-5-phenyl-Pro using EDAC/HOBT provides amide 5.Deprotection of the amino group and hydrolysis of the boronic esters,provides a compound of formula II, 6.

This synthetic scheme is adaptable for the preparation of all thecompounds of the invention, by reacting the appropriate cyclic amine(pyrrollidine, piperidine, and other cyclic amines) withsec-BuLi/B(OCH₃)₃, and coupling the boronic ester intermediate with thedesired acid chloride or acid via routes A or B, respectively. Theappropriate cyclic amine may either be commercially available or iseasily synthesized through known procedures, for example, thoseprocedures disclosed in U.S. Pat. Nos. 6,617,340; 6,432,969; 6,380,398;6,172,081; 6,166,063; 6,124,305; 6,110,949; 6,107,317; 6,011,155; and6,395,767, which are hereby incorporated by reference in their entirety.

Thus, another aspect of the invention provides a process for preparingthe compounds of formula I:

by coupling a reactive compound of formula:

with an amine of formula: R⁵—NH₂; optionally deprotecting the boronicacid ester; and recovering the resultant compound as a free acid or asan acid addition salt; wherein L is a leaving group. R¹, R², R³, R⁴,R^(i), R^(ii), n, X, and Z are as defined herein. Preferred embodimentsare those where R³ and R⁴ are hydrogen, L is halogen, including but notlimited to Cl, and R⁵—NH₂ is cyclopentylamine.

Still another aspect of the invention provides a process for preparingthe compounds of formula II:

by coupling a 2-boroheterocycle having the formula:

with the corresponding N-protected cyclic amino acid; optionallydeprotecting the boronic acid ester; and recovering the resultantcompound as a free acid or as an acid addition salt. R¹ and R² are nothydrogen, and n, X, and Z are as defined herein. Typically the2-boroheterocycle is a 2-boropyrrolidino or 2-boropiperidino. In somesuch embodiments, the N-protected cyclic amino acid isN-Boc-4-phenyl-boroPro-OH.

The compounds of the invention may be prepared in the form ofpharmaceutically acceptable salts, especially acid-addition salts,including salts of organic acids and mineral acids. Examples of suchsalts include salts of organic acids such as formic acid, fumaric acid,acetic acid, propionic acid, glycolic acid, lactic acid, pyruvic acid,oxalic acid, succinic acid, malic acid, tartaric acid, citric acid,benzoic acid, salicylic acid and the like. Suitable inorganicacid-addition salts include salts of hydrochloric, hydrobromic,sulphuric and phosphoric acids and the like. Further examples ofpharmaceutically acceptable inorganic or organic acid addition saltsinclude the pharmaceutically acceptable salts listed in Journal ofPharmaceutical Science, 66, 2 (1977) which are known to the skilledartisan.

The acid addition salts may be obtained as the direct products ofcompound synthesis. In the alternative, the free base may be dissolvedin a suitable solvent containing the appropriate acid, and the saltisolated by evaporating the solvent or otherwise separating the salt andsolvent.

The compounds of this invention may form solvates with standard lowmolecular weight solvents, including water to yield hydrates, usingmethods known to the skilled artisan.

It is to be understood that the invention extends to all of thestereoisomeric forms of the claimed compounds, including enantiomers anddiastereomers, as well as the racemates.

Methods/Uses

Another aspect of the invention provides methods and uses for thecompounds of the invention. In one approach, the invention compounds canbe administered to an individual suffering from a disease or conditionmediated by a post-proline/alanine cleaving amino-dipeptidase. In thisembodiment, the individual is administered an amount of the inventioncompound effective in reducing the activity of the post-proline/alaninecleaving amino-dipeptidase and, thereby, reducing or alleviatingsymptoms of the disease or condition. In some embodiments, theadministered compound reduces the activtity of DPP-IV. In someembodiments, the disease or condition is selected from the groupconsisting of diabetes, diabetec complications, hyperglycemia, SyndromeX, hyperinsulinemia, obesity, atherosclerosis and related diseases. Theinvention compounds to be administered may be one or more of theinventive bronic acid compounds, which may be formulated in any manneras described here, including combination with “other type(s) oftherapeutic agents” identified further below.

Other exemplary embodiments of the invention methods are represented by:

Methods for inhibiting DPP-IV comprising administering to a mammal inneed of such treatment a therapeutically effective amount of a compoundof the invention, or a pharmaceutically acceptable acid addition saltthereof;

Methods for treating conditions mediated by DPP-IV comprisingadministering to a mammal in need of such treatment a therapeuticallyeffective amount of a compound of the invention, or a pharmaceuticallyacceptable acid addition salt thereof;

Methods for treating controlling, or preventing diabetes comprisingadministering to a patient of an effective amount of a compound of theinvention;

Methods for treating, controlling, or preventing insulin dependent (TypeI) and/or non-insulin dependent (Type 2) diabetes mellitus in amammalian patient in need of such treatment, comprising administering tothe patient a therapeutically effective amount of a compound of theinvention;

Methods for treating, controlling or preventing hyperglycemia in amammalian patient in need of such treatment, comprising administering tothe patient a therapeutically effective amount of a compound of theinvention;

Methods for treating, controlling or preventing obesity in a mammalianpatient in need of such treatment, comprising administering to thepatient a therapeutically effective amount of a compound of theinvention;

Methods for treating to enhance islet neogenesis, b-cell survival, andinsulin biosynthesis in a mammalian patient in need of such treatment,comprising administering to the patient a therapeutically effectiveamount of a compound of the invention;

Methods for treating, controlling or preventing insulin resistance in amammalian patient in need of such treatment, comprising administering tothe patient a therapeutically effective amount of a compound of theinvention;

Methods for treating, controlling or preventing one or more lipiddisorders selected from the group consisting of dyslipidemia,hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, low HDL, andhigh LDL in a mammalian patient in need of such treatment, comprisingadministering to the patient a therapeutically effective amount of acompound of the invention;

Methods for treating, controlling or preventing atherosclerosis in amammalian patient in need of such treatment, comprising administering tothe patient a therapeutically effective amount of a compound of theinvention;

Methods for treating or controlling growth hormone deficiency in amammalian patient in need of such treatment, comprising administering tothe patient a therapeutically effective amount of a compound of theinvention;

Methods for modulating the immune response in a mammalian patient inneed of such treatment, comprising administering to the patient atherapeutically effective amount of a compound of the invention;

Methods for treating, or controlling HIV infection in a mammalianpatient in need of such treatment, comprising administering to thepatient a therapeutically effective amount of a compound of theinvention;

Methods for treating, controlling or preventing in a mammalian patientin need of such treatment one or more disorders selected from the groupconsisting of neutropenia, anemia, neuronal disorders, tumor growth andmetastasis, benign prostatic hypertrophy, gingivitis, hypertension andosteoporosis, comprising administering to the patient a therapeuticallyeffective amount of a compound of the invention;

Methods for reducing sperm motility in a male in a mammalian patient inneed of such treatment, comprising administering to the patient atherapeutically effective amount of a compound of the invention;

Methods for treating, controlling or preventing in a mammalian patientin need of such treatment one or more conditions selected from the groupconsisting of (1) hyperglycemia, (2) low glucose tolerance, (3) insulinresistance, (4) obesity, (5) lipid disorders, (6) dyslipidemia, (7)hyperlipidemia, (8) hypertriglyceridemia, (9) hypercholesterolemia, (10)low HDL levels, (11) high LDL levels, (12) atherosclerosis and itssequelae, (13) vascular restenosis, (14) irritable bowel syndrome, (15)inflammatory bowel disease, including Crohn's disease and ulcerativecolitis, (16) rheumatoid arthritis, (17) other inflammatory conditions,(18) pancreatitis, (19) abdominal obesity, (20) neurodegenerativedisease, (21) multiple sclerosis, (22) retinopathy, (23) nephropathy,(24) neuropathy, (25) Syndrome X, (26) ovarian hyperandrogenism, (27)allograft rejection in transplantation, and other conditions whereinsulin resistance is a component, comprising administering to thepatient a therapeutically effective amount of a compound of theinvention;

Methods for treating, controlling or preventing in a mammalian patientin need of such treatment one or more conditions selected from the groupconsisting of (1) hyperglycemia, (2) low glucose tolerance, (3) insulinresistance, (4) obesity, (5) lipid disorders, (6) dyslipidemia, (7)hyperlipidemia, (8) hypertriglyceridemia, (9) hypercholesterolemia, (10)low HDL levels, (11) high LDL levels, (12) atherosclerosis and itssequelae, (13) vascular restenosis, (14) irritable bowel syndrome, (15)inflammatory bowel disease, including Crohn's disease and ulcerativecolitis, (16) rheumatoid arthritis, (17) other inflammatory conditions,(18) pancreatitis, (19) abdominal obesity, (20) neurodegenerativedisease, (21) multiple sclerosis, (22) retinopathy, (23) nephropathy,(24) neuropathy, (25) Syndrome X, (26) ovarian hyperandrogenism, (27)allograft rejection in transplantation, (28) Type II diabetes, (29)growth hormone deficiency, (30) neutropenia, (31) anemia, (32) neuronaldisorders, (33) tumor growth and metastasis, (34) benign prostatichypertrophy, (35) gingivitis, (36) hypertension, (37) osteoporosis, andother conditions that may be treated by inhibition of dipeptidylpeptidase-IV, comprising administering to the patient of atherapeutically effective amount of a first compound of the invention,or a pharmaceutically acceptable salt thereof, and one or more othercompounds selected from the group consisting of

a) Other dipeptidyl peptidase-IV inhibitors;

b) Insulin sensitizers selected from the group consisting of (i) PPARagonists, (ii) biguanides, and (iii) protein phosphatase-1B inhibitors;

c) Insulin or insulin mimetics;

d) Sulfonylureas or other insulin secretagogues;

e) α-glucosidase inhibitors;

f) glucagons receptor agonists;

g) GLP-1, GLP-1 mimetics, and GLP-1 receptor agonists;

h) GLP-2, GLP-2 mimetics, and GLP-2 receptor agonists;

i) GIP, GIP mimetics, and GIP receptor agonists;

j) PACAP, PACAP mimetics, and PACAP receptor 3 agonists;

k) Cholesterol lowering agents selected from the group consisting of (i)HMG-CoA reductase inhibitors, (ii) sequestrants, (iii) nicotinylalcohol, nicotinic acid or a salt thereof, (iv) PPARα agonists, (v)PPARα/γ dual agonists, (vi) inhibitors of cholesterol absorption, (vii)acyl CoA:cholesterol acyltransferase inhibitors, and (viii)anti-oxidants;

l) PPAR agonists;

m) Anti-obesity compounds;

n) An ileal bile acid transporter inhibitor;

o) Anti-inflammatory agents;

p) G-CSF, G-CSF mimetics, and G-CSF receptor agonists; and

q) EPO, EPO mimetics, and EPO receptor agonists.

Methods for the treatment, control, or prevention of one or moreconditions selected from the group consisting of hypercholesterolemia,atherosclerosis, low HDL levels, high LDL levels, hyperlipidemia,hypertriglyceridemia, and dyslipidemia, comprising administering to amammalian patient in need of such treatment a therapeutically effectiveamount of a compound of the invention and an HMG-CoA reductaseinhibitor;

Methods wherein the HMC-CoA reductase inhibitor is a statin;

Methods wherein the statin is selected from the group consisting oflovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin,itavastatin, ZD-4522 and rivastatin;

Methods for treating, controlling or preventing atherosclerosis,comprising administering to a mammalian patient in need of suchtreatment a therapeutically effective amount of a compound of theinvention and an HMG-CoA reductase inhibitor;

Methods for treating, controlling or preventing obesity, comprisingadministering to a mammalian patient in need of such treatment atherapeutically effective amount of a compound of the invention and ananti-obesity agent;

Methods wherein the anti-obesity agent is a beta-3 adrenergic agonist, alipase inhibitor, a serotonin (and dopamine) reuptake inhibitor, athyroid receptor beta compound, an anorectic agent, and/or a fatty acidoxidation upregulator;

Methods wherein the anti-obesity agent is orlistat, ATL-962, AJ9677,L750355, CP331648, sibutramine, topiramate, axokine, dexamphetamine,phentermine, phenylpropanolamine, famoxin, and/or mazindol;

Methods for the treatment, control, or prevention of neutropeniacomprising administering to a mammalian patient in need of suchtreatment a therapeutically effective amount of a compound of theinvention and a neutrophilic agent;

Methods for the treatment, control, or prevention of neutropenia whereinthe neutrophilic agent is G-CSF, a G-CSF mimetic, or a G-CSF receptoragonist;

Methods for the treatment, control, or prevention of neutropenia whereinthe neutrophilic agent is pegfilgrastim, filgrastim, lenograstim, ornartograstim;

Methods for the treatment, control, or prevention of anemia, comprisingadministering to a mammalian patient in need of such treatment atherapeutically effective amount of a compound of the invention and aerythropoietin agonist;

Methods for the treatment, control, or prevention of anemia wherein theerythropoietin agonist is EPO, an EPO mimetic, or an EPO receptoragonist;

Methods for the treatment, control, or prevention of anemia wherein theerythropoietin agonist is epoetin alfa, or darbepoetin alfa;

Methods for treating diabetes, insulin resistance, hyperglycemia,hyperisulinemia, or elevated blood levels of free fatty acids orglycerol, obesity, Syndrome X, dysmetabolic syndrome, diabeticcomplications, hypertriglyceridemia, hyperinsulinemia, atherosclerosis,impaired glucose homeostasis, impaired glucose tolerance, infertility,polycystic ovary syndrome, growth disorders, frailty, arthritis,allograft rejection in transplantation, autoimmune diseases, AIDS,intestinal diseases, inflammatory bowel syndrome, nervosa, osteoporosis,or an immunomodulatory disease or a chronic inflammatory bowel disease,comprising administering to a mammalian species in need of treatment atherapeutically effective amount of a compound of the invention;

Methods for treating type II diabetes and/or obesity;

A variety of uses of the invention compounds are possible along thelines of the various methods of the treating an individual such as amammal described above. Exemplary uses of the invention methods arerepresented by:

Use of a compound of the invention for the manufacture of a medicamentfor treating a condition that may be regulated or normalized viainhibition of DPP-IV;

Use of a compound of the invention for the manufacture of a medicamentfor treatment of metabolic disorders;

Use of a compound of the invention for the manufacture of a medicamentfor blood glucose lowering;

Use of a compound of the invention for the manufacture of a medicamentfor treatment of type II diabetes;

Use of a compound of the invention for the manufacture of a medicamentfor the treatment of impaired glucose tolerance (IGT);

Use of a compound of the invention for the manufacture of a medicamentfor the treatment of impaired fasting glucose (IFG);

Use of a compound of the invention for the manufacture of a medicamentfor prevention of hyperglycemia;

Use of a compound of the invention for the manufacture of a medicamentfor delaying the progression of impaired glucose tolerance (IGT) to typeII diabetes;

Use of a compound of the invention for the manufacture of a medicamentfor delaying the progression of non-insulin requiring type II diabetesto insulin requiring type II diabetes;

Use of a compound of the invention for the manufacture of a medicamentfor increasing the number and/or the size of beta cells in a mammaliansubject;

Use of a compound of the invention for the manufacture of a medicamentfor treatment of beta cell degeneration, in particular apoptosis of betacells.

Use of a compound of the invention for the manufacture of a medicamentfor the treatment of disorders of food intake;

Use of a compound of the invention for the manufacture of a medicamentfor the treatment of obesity;

Use of a compound of the invention for the manufacture of a medicamentfor appetite regulation or induction of satiety;

Use of a compound of the invention for the manufacture of a medicamentfor the treatment of dyslipidemia;

Use of a compound of the invention for the manufacture of a medicamentfor treatment of functional dyspepsia, in particular irritable bowelsyndrome; and

Methods for treating the conditions mentioned above by administering toa subject in need thereof an effective amount of a compound of theinvention.

Combination Treatments

The compounds of the invention may be used in combination with one ormore other types of antidiabetic agents (employed to treat diabetes andrelated diseases) and/or one or more other types of therapeutic agentswhich may be administered orally in the same dosage form, in a separateoral dosage form or by injection.

The other type of antidiabetic agent which may be optionally employed incombination with the DPP-IV inhibitors of the invention may be 1,2,3 ormore antidiabetic agents or antihyperglycemic agents including insulinsecretagogues or insulin sensitizers, or other antidiabetic agentspreferably having a mechanism of action different from DPP-IV inhibitionand may include biguanides, sulfonyl ureas, glucosidase inhibitors, PPARγ agonists, such as thiazolidinediones, SGLT2 inhibitors, PPAR α/γ dualagonists, aP2 inhibitors, glycogen phosphorylase inhibitors, advancedglycosylation end (AGE) products inhibitors, and/or meglitinides, aswell as insulin, and/or glucagon-like peptide-1 (GLP-1) or mimeticsthereof.

The use of the compounds of the invention in combination with 1, 2, 3 ormore other antidiabetic agents may produce antihyperglycemic resultsgreater than that possible from each of these medicaments alone andgreater than the combined additive antihyperglycemic effects produced bythese medicaments.

The other antidiabetic agent may be an oral antihyperglycemic agentpreferably a biguanide such as metformin or phenformin or salts thereof,preferably metformin HCl.

Where the other antidiabetic agent is a biguanide, the compounds of theinvention will be employed in a weight ratio to biguanide within therange from about 0.01:1 to about 100:1, preferably from about 0.1:1 toabout 5:1.

Preferably, the other antidiabetic agent can be a sulfonyl urea such asglyburide (also known as glibenclamide), glimepiride (disclosed in U.S.Pat. No. 4,379,785), glipizide, gliclazide or chlorpropamide, otherknown sulfonylureas or other antihyperglycemic agents which act on theATP-dependent channel of the γ-cells, with glyburide and glipizide beingpreferred, which may be administered in the same or in separate oraldosage forms.

The compounds of the invention will be employed in a weight ratio to thesulfonyl urea in the range from about 0.01:1 to about 100:1, preferablyfrom about 0.05:1 to about 5:1.

The oral antidiabetic agent may also be a glucosidase inhibitor such asacarbose (disclosed in U.S. Pat. No. 4,904,769) or miglitol (disclosedin U.S. Pat. No. 4,639,436), which may be administered in the same or ina separate oral dosage forms.

The compounds of the invention will be employed in a weight ratio to theglucosidase inhibitor within the range from about 0.01:1 to about 100:1,preferably from about 0.2:1 to about 50:1.

The compounds of the invention may be employed in combination with aPPAR y agonist such as a thiazolidinedione oral anti-diabetic agent orother insulin sensitizers (which has an insulin sensitivity effect inNIDDM patients) such as troglitazone (Warner-Lambert's Rezulin®,disclosed in U.S. Pat. No. 4,572,912), rosiglitazone (en), pioglitazone(Takeda), Mitsubishi MCC-555 (disclosed in U.S. Pat. No. 5,594,016),Glaxo-Wellcome's GL-262570, englitazone (CP-68722, Pfizer) ordarglitazone (CP-86325, Pfizer), isaglitazone (MIT/J&J), JTT-501(JPNT/P&U), L-895645 (Merck), R-119702 (Sankyo/WL), NN-2344 (Dr.Reddy/NN), or YM-440 (Yamanouchi), preferably rosiglitazone andpioglitazone.

The compounds of the invention will be employed in a weight ratio to thethiazolidinedione in an amount within the range from about 0.01:1 toabout 100:1, preferably from about 0.1:1 to about 10:1.

The sulfonyl urea and thiazolidinedione in amounts of less than about150 mg oral antidiabetic agent may be incorporated in a single tabletwith the compounds of the invention.

The compounds of the invention may also be employed in combination witha antihyperglycemic agent such as insulin or with glucagon-likepeptide-1 (GLP-1) such as GLP-1(1-36) amide, GLP-1(7-36) amide,GLP-1(7-36) (as disclosed in U.S. Pat. No. 5,614,492 to Habener,disclosure of which is incorporated herein by reference), or a GLP-1mimic such as AC2993 or Exendin-4 (Amylin) and LY-315902 or LY-307167(Lilly) and NN2211 (Novo-Nordisk), which may be administered viainjection, intranasal, or by transdermal or buccal devices.

Where present, metformin, the sulfonyl ureas, such as glyburide,glimepiride, glipyride, glipizide, chlorpropamide and gliclazide and theglucosidase inhibitors acarbose or miglitol or insulin (injectable,pulmonary, buccal, or oral) may be employed in formulations as describedabove and in amounts and dosing as indicated in the PHYSICIAN'S DESKREFERENCE (PDR).

Where present, metformin or salt thereof may be employed in amountswithin the range from about 500 to about 2000 mg per day which may beadministered in single or divided doses one to four times daily.

Where present, the thiazolidinedione anti-diabetic agent may be employedin amounts within the range from about 0.01 to about 2000 mg/day whichmay be administered in single or divided doses one to four times perday.

Where present insulin may be employed in formulations, amounts anddosing as indicated by the PHYSICIAN'S DESK REFERENCE.

Where present GLP-1 peptides may be administered in oral buccalformulations, by nasal administration (for example inhalation spray) orparenterally as described in U.S. Pat. No. 5,346,701 (TheraTech), U.S.Pat. Nos. 5,614,492 and 5,631,224 which are incorporated herein byreference.

The other antidiabetic agent may also be a PPAR α/γ dual agonist such asAR-H039242 (Astra/Zeneca), GW-409544 (Glaxo-Wellcome), KRP297 (KyorinMerck), as well as those disclosed by Murakami et al., “A Novel InsulinSensitizer Acts As a Coligand for Peroxisome Proliferation—ActivatedReceptor Alpha (PPAR alpha) and PPAR gamma. Effect on PPAR alphaActivation on Abnormal Lipid Metabolism in Liver of Zucker Fatty Rats,”Diabetes 47: 1841-47 (1998), and in U.S. application Ser. No.09/664,598, filed Sep. 18, 2000, (attorney file LA29NP), the disclosureof which is incorporated herein by reference, employing dosages as setout therein, which compounds designated as preferred are preferred foruse herein.

The other antidiabetic agent may be an SGLT2 inhibitor, as disclosed inU.S. application Ser. No. 09/679,027, filed Oct. 4, 2000 (attorney fileLA49NP), which is incorporated herein by reference, employing dosages asset out herein. Preferred are the compounds designated as preferred inthe above application.

The other antidiabetic agent, which may be employed in combination withthe DPP-IV inhibitors in accordance with the present invention, can bean aP2 inhibitor, Ser. No. 09/519,079, filed Mar. 6, 2000 (attorney fileLA27NP), which are each incorporated herein by reference, employingdosages as set out herein. Preferred antidiabetic agents to be used incombination with the invention compounds are those indicated aspreferred in the above cited patents.

The other antidiabetic agent that may employed with the DPP-IVinhibitors of the invention can be a glycogen phosphorylase inhibitor asdisclosed, for instance, in WO 96/39384, WO 96/39385, WO 99/26659, WO99/43663, WO 2000/47206, EP 978279, EP 1041068, and U.S. Pat. No.5,952,322 and No. 5,998,463.

The meglitinide which may optionally be employed in combination with thecompound of the invention may be repaglinide, nateglinide (Novartis) orKAD1229(PF/Kissei), with repaglinide being preferred.

The DPP-IV inhibitors of the invention will be employed in a weightratio to the meglitinide, PPAR y agonist, PPAR α/γ dual agonist, SGLT2inhibitor, aP2 inhibitor, or glycogen phosphorylase inhibitor within therange from about 0.01:1 to about 100:1, preferably from about 0.1:1 toabout 10:1.

The hypolipidemic agent or lipid-modulating agent which may beoptionally employed in combination with the compounds of the inventionmay include 1,2,3 or more MTP inhibitors, HMG CoA reductase inhibitors,squalene synthetase inhibitors, fibric acid derivatives, ACATinhibitors, lipoxygenase inhibitors, cholesterol absorption inhibitors,ileal Na+/bile acid cotransporter inhibitors, upregulators of LDLreceptor activity, ATP citrate lyase inhibitors, cholesteryl estertransfer protein inhibitors, bile acid sequestrants, and/or nicotinicacid and derivatives thereof.

MTP inhibitors employed herein include MTP inhibitors disclosed in U.S.Pat. No. 5,595,872, No. 5,739,135, No. 5,712,279, No. 5,760,246, No.5,827,875, No. 5,885,983, and No. 5,962,440. MTP inihibitors preferredherein are those identified as being preferred in the above referencedpatents.

Most preferred MTP inhibitors, in accordance with the present invention,are implitapide (Bayer) and those set out in U.S. Pat. No. 5,739,135,No. 5,712,279, and No. 5,760,246. A particularly preferred MTP inhibitorin this context is9-[4-[4-[[2-(2,2,2-Trifluoroethoxy)-benzoyl]amino]-1-piperidinyl]butyl]-N-(2,2,2-trifluoroethyl)-9H-fluorene-9-carboxamide.

The hypolipidemic agent may be an HMG CoA reductase inhibitor whichincludes, but is not limited to, mevastatin and related compounds asdisclosed in U.S. Pat. No. 3,983,140, lovastatin (mevinolin) and relatedcompounds disclosed in U.S. Pat. No. 4,231,938, pravastatin and relatedcompounds such as disclosed in U.S. Pat. No. 4,346,227, simvastatin andrelated compounds as disclosed in U.S. Pat. Nos. 4,448,784 and4,450,171. Other HMG CoA reductase inhibitors which may be employedherein include, but are not limited to, fluvastatin, disclosed in U.S.Pat. No. 5,354,772, cerivastatin disclosed in U.S. Pat. No. 5,006,530and No. 5,177,080, atorvastatin disclosed in U.S. Pat. No. 4,681,893,No. 5,273,995, No. 5,385,929 and No. 5,686,104, atavastatin(Nissan/Sankyo nisvastatin (NK-104)), disclosed in U.S. Pat. No.5,011,930, and Shionogi-Astra/Zeneca visastatin (ZD-4522), disclosed inU.S. Pat. No. 5,260,440.

The squalene synthetase inhibitors suitable for use herein include, butare not limited to, α-phosphono-sulfonates disclosed in U.S. Pat. No.5,712,396, those disclosed by Biller et al, J. Med. Chem., 1988, Vol.11, No. 10, pp 1869-1871, including isoprenoid(phosphinyl-methyl)phosphonates as well as other known squalenesynthetase inhibitors, for example, as disclosed in U.S. Pat. Nos.4,871,721 and 4,924,024 and in Biller, S. A., Neuenschwander, K.,Ponpipom, M. M., and Poulter, C. D., Current Pharmaceutical Design, 2,1-40 (1996).

In addition, other squalene synthetase inhibitors suitable for useherein include the terpenoid pyrophosphates disclosed by P. Ortiz deMontellano et al, J. Med. Chem., 1977, 20, 243-249, the farnesyldiphosphate analog A and presqualene pyrophosphate (PSQ-PP) analogs asdisclosed by Corey and Volante, J. Am. Chem. Soc., 1976, 98, 1291-1293,phosphinylphosphonates reported by McClard, R. W. et al, J.A.C.S., 1987,10, 5544 and cyclopropanes reported by Capson, T. L., PhD dissertation,June, 1987, Dept. Med. Chem. U of Utah, Abstracts Table of Contents, pp16, 17, 40-43, 48-51, Summary.

Other hypolipidemic agents suitable for use herein include, but are notlimited to, fibric acid derivatives, such as fenofibrate, gemfibrozil,clofibrate, bezafibrate, ciprofibrate, clinofibrate, and the like,probucol, and related compounds as disclosed in U.S. Pat. No. 3,674,836,probucol and gemfibrozil being preferred, bile acid sequestrants such ascholestyramine, colestipol and DEAE-Sephadex (Secholex®, Policexide®),as well as lipostabil (Rhone-Poulenc), Eisai E-5050 (an N-substitutedethanolamine derivative), imanixil (HOE-402), tetrahydrolipstatin (THL),istigmastanylphos-phorylcholine (SPC, Roche), aminocyclodextrin (TanabeSeiyoku), Ajinomoto AJ-814 (azulene derivative), melinamide (Sumitomo),Sandoz 58-035, American Cyanamid CL-277,082 and CL-283,546(disubstituted urea derivatives), nicotinic acid, acipimox, acifran,neomycin, p-aminosalicylic acid, aspirin, poly(diallylmethylamine)derivatives such as disclosed in U.S. Pat. No. 4,759,923, quaternaryamine poly(diallyldimethylammonium chloride) and ionenes such asdisclosed in U.S. Pat. No. 4,027,009, and other known serum cholesterollowering agents.

The other hypolipidemic agent may be an ACAT inhibitor such as disclosedin 24 DRUGS OF THE FUTURE 9-15 (Avasimibe 1999), “The ACAT inhibitor,Cl-1011 is effective in the prevention and regression of aortic fattystreak area in hamsters”, Nicolosi et al, Atherosclerosis (Shannon,Irel). (1998), 137(1), 77-85; “The pharmacological profile of FCE 27677:a novel ACAT inhibitor with potent hypolipidemic activity mediated byselective suppression of the hepatic secretion of ApoB100-containinglipoprotein”, Ghiselli, Giancarlo, Cardiovasc. Drug Rev. (1998), 16(1),16-30; “RP 73163: a bioavailable alkylsulfinyl-diphenylimidazole ACATinhibitor”, Smith, C., et al, Bioorg. Med. Chem. Lett. (1996), 6(1),47-50; “ACAT inhibitors: physiologic mechanisms for hypolipidemic andanti-atherosclerotic activities in experimental animals”, Krause et al,Editor(s): Ruffolo, Robert R., Jr.; Hollinger, Mannfred A.,Inflammation: Mediators Pathways (1995), 173-98, Publisher: CRC, BocaRaton, Fla.; “ACAT inhibitors: potential anti-atherosclerotic agents”,Sliskovic et al, Curr. Med. Chem. (1994), 1(3), 204-25; “Inhibitors ofacyl-CoA:cholesterol O-acyl transferase (ACAT) as hypocholesterolemicagents. 6. The first water-soluble ACAT inhibitor with lipid-regulatingactivity. Inhibitors of acyl-CoA:cholesterol acyltransferase (ACAT). 7.Development of a series of substitutedN-phenyl-N′-[(1-phenylcyclopentyl)methyl]ureas with enhancedhypocholesterolemic activity”, Stout et al, Chemtracts: Org. Chem.(1995), 8(6), 359-62, or TS-962 (Taisho Pharmaceutical Co. Ltd).

The hypolipidemic agent may be an upregulator of LD2 receptor activitysuch as MD-700 (Taisho Pharmaceutical Co. Ltd) and LY295427 (Eli Lilly).

The hypolipidemic agent may be a cholesterol absorption inhibitorpreferably Schering-Plough's SCH48461 as well as those disclosed inAtherosclerosis 115, 45-63 (1995) and J. Med. Chem. 41, 973 (1998).

The hypolipidemic agent may be an ileal Na⁺/bile acid cotransporterinhibitor such as disclosed in Drugs of the Future, 24, 425-430 (1999).

The lipid-modulating agent may be a cholesteryl ester transfer protein(CETP) inhibitor such as Pfizer's CP 529,414 (WO/0038722 and EP 818448)and Pharmacia's SC-744 and SC-795.

The ATP citrate lyase inhibitor which may be employed in the combinationof the invention may include, for example, those disclosed in U.S. Pat.No. 5,447,954.

Preferred hypolipidemic agents are pravastatin, lovastatin, simvastatin,atorvastatin, fluvastatin, cerivastatin, atavastatin and ZD-4522.

The above-mentioned U.S. patents are incorporated herein by reference.The amounts and dosages employed will be as indicated in the Physician'sDesk Reference and/or in the patents set out above.

The compounds of the invention will be employed in a weight ratio to thehypolipidemic agent (where present), within the range from about 500:1to about 1:500, preferably from about 100:1 to about 1:100.

The dose administered must be carefully adjusted according to age,weight and condition of the patient, as well as the route ofadministration, dosage form and regimen and the desired result.

The dosages and formulations for the hypolipidemic agent will be asdisclosed in the various patents and applications discussed above.

The dosages and formulations for the other hypolipidemic agent to beemployed, where applicable, will be as set out in the latest edition ofthe Physicians' Desk Reference.

For oral administration, a satisfactory result may be obtained employingthe MTP inhibitor in an amount within the range of from about 0.01 mg/kgto about 500 mg and preferably from about 0.1 mg to about 100 mg, one tofour times daily.

An oral dosage form, such as tablets or capsules, will contain the MTPinhibitor in an amount of from about 1 to about 500 mg, preferably fromabout 2 to about 400 mg, and more preferably from about 5 to about 250mg, one to four times daily.

For oral administration, a satisfactory result may be obtained employingan HMG CoA reductase inhibitor, for example, pravastatin, lovastatin,simvastatin, atorvastatin, fluvastatin or cerivastatin in dosagesemployed as indicated in the PHYSICIAN'S DESK REFERENCE, such as in anamount within the range of from about 1 to 2000 mg, and preferably fromabout 4 to about 200 mg.

The squalene synthetase inhibitor may be employed in dosages in anamount within the range of from about 10 mg to about 2000 mg andpreferably from about 25 mg to about 200 mg.

A preferred oral dosage form, such as tablets or capsules, will containthe HMG CoA reductase inhibitor in an amount from about 0.1 to about 100mg, preferably from about 5 to about 80 mg, and more preferably fromabout 10 to about 40 mg.

A preferred oral dosage form, such as tablets or capsules will containthe squalene synthetase inhibitor in an amount of from about 10 to about500 mg, preferably from about 25 to about 200 mg.

The other hypolipidemic agent may also be a lipoxygenase inhibitorincluding a 15-lipoxygenase (15-LO) inhibitor such as benzimidazolederivatives as disclosed in WO 97/12615, 15-LO inhibitors as disclosedin WO 97/12613, isothiazolones as disclosed in WO 96/38144, and 15-LOinhibitors as disclosed by Sendobry et al “Attenuation of diet-inducedatherosclerosis in rabbits with a highly selective 15-lipoxygenaseinhibitor lacking significant antioxidant properties”, Brit. J.Pharmacology (1997) 120, 1199-1206, and Cornicelli et al,“15-Lipoxygenase and its Inhibition: A Novel Therapeutic Target forVascular Disease”, Current Pharmaceutical Design, 1999, 5, 11-20.

The compounds of the invention and the hypolipidemic agent may beemployed together in the same oral dosage form or in separate oraldosage forms taken at the same time.

The compositions described above may be administered in the dosage formsas described above in single or divided doses of one to four timesdaily. It may be advisable to start a patient on a low dose combinationand work up gradually to a high dose combination.

The preferred hypolipidemic agent is pravastatin, simvastatin,lovastatin, atorvastatin, fluvastatin or cerivastatin.

The other type of therapeutic agent which may be optionally employedwith the DPP-IV inhibitors of the invention may be 1, 2, 3 or more of ananti-obesity agent including a beta 3 adrenergic agonist, a lipaseinhibitor, a serotonin (and dopamine) reuptake inhibitor, a thyroidreceptor beta drug, an anorectic agent and/or a fatty acid oxidationupregulator.

The beta 3 adrenergic agonist which may be optionally employed incombination with a compound of the invention may be AJ9677(Takeda/Dainippon), L750355 (Merck), or CP331648 (Pfizer) or other knownbeta 3 agonists as disclosed in U.S. Pat. No. 5,541,204, No. 5,770,615,No. 5,491,134, No. 5,776,983 and No. 5,488,064, with AJ9677, L750,355and CP331648 being preferred.

The lipase inhibitor which may be optionally employed in combinationwith a compound of the invention may be orlistat or ATL-962 (Alizyme),with orlistat being preferred.

The serotonin (and dopamine) reuptake inhibitor which may be optionallyemployed in combination with a compound of the invention may besibutramine, topiramate (Johnson & Johnson) or axokine (Regeneron), withsibutramine and topiramate being preferred.

The thyroid receptor beta compound which may be optionally employed incombination with a compound of the invention may be a thyroid receptorligand as disclosed in W097/21993 (U. Cal SF), W0099/00353 (KaroBio) andGB98/284425 (KaroBio), with compounds of the KaroBio applications beingpreferred.

The anorectic agent which may be optionally employed in combination witha compound of the invention may be dexamphetamine, phentermine,phenylpropanolamine or mazindol, with dexamphetamine being preferred.

The fatty acid oxidation upregulator which may be optionally employed incombination with the compound of the invention can be famoxin (Genset).

The various anti-obesity agents described above may be employed in thesame dosage form with the compound of the invention or in differentdosage forms, in dosages and regimens as generally known in the art orin the PDR.

The infertility agent which may be optionally employed in combinationwith the DPP-IV inhibitor of the invention may be 1, 2, or more ofclomiphene citrate (Clomid®, Aventis), bromocriptine mesylate(Parlodel®, Novartis), LHRH analogs, Lupron (TAP Pharm.), danazol,Danocrine (Sanofi), progestogens or glucocorticoids, which may beemployed in amounts specified in the PDR.

The agent for polycystic ovary syndrome which may be optionally employedin combination with the DPP-IV inhibitor of the invention may be 1, 2,or more of gonadotropin releasing hormone (GnRH), leuprolide (Lupron®),Clomid®, Parlodel®, oral contraceptives or insulin sensitizers such asPPAR agonists, or other conventional agents for such use which may beemployed in amounts specified in the PDR.

The agent for treating growth disorders and/or frailty which may beoptionally employed in combination with the DPP-IV inhibitor of theinvention may be 1, 2, or more of a growth hormone or growth hormonesecretagogue such as MK-677 (Merck), CP-424,391 (Pfizer), and compoundsdisclosed in U.S. Ser. No. 09/506,749 filed Feb. 18, 2000 (attorneydocket LA26), as well as selective androgen receptor modulators (SARMs),which is incorporated herein by reference, which may be employed inamounts specified in the PDR, where applicable.

The agent for treating arthritis which may be optionally employed incombination with the DPP-1V inhibitor of the invention may be 1, 2, ormore of aspirin, indomethacin, ibuprofen, diclofenac sodium, naproxen,nabumetone (Relafen®, SmithKline Beecham), tolmetin sodium (Tolectin®,Ortho-McNeil), piroxicam (Feldene®, Pfizer), ketorolac tromethamine(Toradol®, Roche), celecoxib (Celebrex®, Searle), rofecoxib (Vioxx®,Merck) and the like, which may be employed in amounts specified in thePDR.

Conventional agents for preventing allograft rejection intransplantation such as cyclosporin, Sandimmune (Novartis),azathioprine, Immuran (Faro) or methotrexate may be optionally employedin combination with the DPP-IV inhibitor of the invention, which may beemployed in amounts specified in the PDR.

Conventional agents for treating autoimmune diseases such as multiplesclerosis and immunomodulatory diseases such as lupus erythematosis,psoriasis, for example, azathioprine, Immuran, cyclophosphamide, NSAIDSsuch as ibuprofen, cox 2 inhibitors such as Vioxx and Celebrex,glucocorticoids and hydroxychloroquine, may be optionally employed incombination with the DPP-IV inhibitor of the invention, which may beemployed in amounts specified in the PDR.

The AIDS agent which may be optionally employed in combination with theDPP-IV inhibitor of the invention may be a non-nucleoside reversetranscriptase inhibitor, a nucleoside reverse transcriptase inhibitor, aprotease inhibitor and/or an AIDS adjunct anti-infective and may be 1,2, or more of dronabinol (Marinol®, Roxane Labs), didanosine (Videx®,Bristol-Myers Squibb), megestrol acetate (Megace®, Bristol-MyersSquibb), stavudine (Zerit®, Bristol-Myers Squibb), delavirdine mesylate(Rescriptor®, Pharmacia), lamivudine/zidovudine (Combivir™, Glaxo),lamivudine (Epivir™, Glaxo), zalcitabine (Hivid®, Roche), zidovudine(Retrovir®, Glaxo), indinavir sulfate (Crixivan®, Merck), saquinavir(Fortovase™, Roche), saquinovir mesylate (Invirase®, Roche), ritonavir(Norvir®, Abbott), nelfinavir (Viracept®, Agouron).

The above anti-AIDS agents may be employed in amounts specified in thePDR.

The agent for treating inflammatory bowel disease or syndrome which maybe optionally employed in combination with the DPP-IV inhibitor of theinvention may be 1, 2, or more of sulfasalazine, salicylates, mesalamine(Asacol®, P&G) or Zelmac®, (Bristol-Myers Squibb), which may be employedin amounts specified in the PDR or otherwise known in the art.

The agent for treating osteoporosis which may be optionally employed incombination with the DPP-IV inhibitor of the invention may be 1, 2, ormore of alendronate sodium (Fosamax®, Merck, tiludronate (Skelid®,Sanofi), etidronate disodium (Didronel®, P&G), raloxifene HCl (Evista®,Lilly), which may be employed in amounts specified in the PDR.

In carrying out the methods of the invention, a pharmaceuticalcomposition may be employed containing the compounds of the invention,with or without another antidiabetic agent and/or other type therapeuticagent, in association with a pharmaceutical vehicle or diluent. Thepharmaceutical composition can be formulated employing conventionalsolid or liquid vehicles or diluents and pharmaceutical additives of atype appropriate to the mode of desired administration. The compoundscan be administered to mammalian species including humans, monkeys,dogs, etc. by an oral route, for example, in the form of tablets,capsules, granules or powders, or they can be administered by aparenteral route in the form of injectable preparations. The dose foradults is preferably between 10 and 1,000 mg per day, which can beadministered in a single dose or in the form of individual doses from1-4 times per day.

A typical capsule for oral administration contains compounds of theinvention (250 mg), lactose (75 mg) and magnesium stearate (15 mg). Themixture is passed through a 60 mesh sieve and packed into a No. 1gelatin capsule. A typical injectable preparation is produced byaseptically placing 250 mg of compounds of the invention into a vial,aseptically freeze-drying and sealing. For use, the contents of the vialare mixed with 2 mL of physiological saline, to produce an injectablepreparation.

DPP-IV inhibitor activity of the compounds of the invention may bedetermined by use of an in vitro assay system which measures thepotentiation of inhibition of DPP-IV. Inhibition constants (Ki values)for the DPP-IV inhibitors of the invention may be determined by themethod described below.

Pharmaceutical Compositions

Pharmaceutical compositions containing a compound of the invention ofthe invention may be prepared by conventional techniques, e.g. asdescribed in Remington: The Science and Practise of Pharmacy, 19th Ed.,1995. The compositions may appear in conventional forms, for examplecapsules, tablets, aerosols, solutions, suspensions or topicalapplications.

Typical compositions include a compound of the invention which inhibitsthe enzymatic activity of DPP-IV or a pharmaceutically acceptable basicaddition salt or prodrug or hydrate thereof, associated with apharmaceutically acceptable excipient which may be a carrier or adiluent or be diluted by a carrier, or enclosed within a carrier whichcan be in the form of a capsule, sachet, paper or other container. Inmaking the compositions, conventional techniques for the preparation ofpharmaceutical compositions may be used. For example, the activecompound will usually be mixed with a carrier, or diluted by a carrier,or enclosed within a carrier which may be in the form of a ampoule,capsule, sachet, paper, or other container. When the carrier serves as adiluent, it may be solid, semi-solid, or liquid material that acts as avehicle, excipient, or medium for the active compound. The activecompound can be adsorbed on a granular solid container for example in asachet. Some examples of suitable carriers are water, salt solutions,alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil,peanut oil, olive oil, gelatin, lactose, terra alba, sucrose, dextrin,magnesium carbonate, sugar, cyclodextrin, amylose, magnesium stearate,talc, gelatin, agar, pectin, acacia, stearic acid or lower alkyl ethersof cellulose, silicic acid, fatty acids, fatty acid amines, fatty acidmonoglycerides and diglycerides, pentaerythritol fatty acid esters,polyoxyethylene, hydroxymethylcellulose and polyvinylpyrrolidone.Similarly, the carrier or diluent may include any sustained releasematerial known in the art, such as glyceryl monostearate or glyceryldistearate, alone or mixed with a wax. The formulations may also includewetting agents, emulsifying and suspending agents, preserving agents,sweetening agents or flavoring agents. The formulations of the inventionmay be formulated so as to provide quick, sustained, or delayed releaseof the active ingredient after administration to the patient byemploying procedures well known in the art.

The pharmaceutical compositions can be sterilized and mixed, if desired,with auxiliary agents, emulsifiers, salt for influencing osmoticpressure, buffers and/or coloring substances and the like, which do notdeleteriously react with the active compounds.

The route of administration may be any route, which effectivelytransports the active compound of the invention which inhibits theenzymatic activity of DPP-IV to the appropriate or desired site ofaction, such as oral, nasal, pulmonary, buccal, subdermal, intradermal,transdermal or parenteral, e.g., rectal, depot, subcutaneous,intravenous, intraurethral, intramuscular, intranasal, ophthalmicsolution or an ointment, the oral route being preferred.

If a solid carrier is used for oral administration, the preparation maybe tabletted, placed in a hard gelatin capsule in powder or pellet formor it can be in the form of a troche or lozenge. If a liquid carrier isused, the preparation may be in the form of a syrup, emulsion, softgelatin capsule or sterile injectable liquid such as an aqueous ornon-aqueous liquid suspension or solution.

For nasal administration, the preparation may contain a compound of theinvention which inhibits the enzymatic activity of DPP-IV, dissolved orsuspended in a liquid carrier, in particular an aqueous carrier, foraerosol application. The carrier may contain additives such assolubilizing agents, e.g., propylene glycol, surfactants, absorptionenhancers such as lecithin (phosphatidylcholine) or cyclodextrin, orpreservatives such as parabenes.

For parenteral application, particularly suitable are injectablesolutions or suspensions, preferably aqueous solutions with the activecompound dissolved in polyhydroxylated castor oil.

Tablets, dragees, or capsules having talc and/or a carbohydrate carrieror binder or the like are particularly suitable for oral application.Preferable carriers for tablets, dragees, or capsules include lactose,corn starch, and/or potato starch. A syrup or elixir can be used incases where a sweetened vehicle can be employed.

A typical tablet that may be prepared by conventional tablettingtechniques may contain:

Core: Active compound (as free compound or salt 250 mg thereof)Colloidal silicon dioxide (Aerosil) ® 1.5 mg Cellulose, microcryst.(Avicel) ® 70 mg Modified cellulose gum (Ac-Di-Sol) ® 7.5 mg Magnesiumstearate Ad. Coating: HPMC approx. 9 mg *Mywacett 9-40 T approx. 0.9 mg*Acylated monoglyceride used as plasticizer for film coating.

The compounds of the invention may be administered to a mammal,especially a human in need of such treatment, prevention, elimination,alleviation or amelioration of the various diseases as mentioned above,e.g., type II diabetes, IGT, IFG, obesity, appetite regulation or as ablood glucose lowering agent, and especially type II diabetes. Suchmammals include also animals, both domestic animals, e.g. householdpets, and non-domestic animals such as wildlife.

The compounds of the invention are effective over a wide dosage range.For example, in the treatment of adult humans, dosages from about 0.05to about 1000 mg, preferably from about 1 to about 500 mg, per day maybe used. A typical dosage is about 10 mg to about 500 mg per day. Inchoosing a regimen for patients it may frequently be necessary to beginwith a higher dosage and when the condition is under control to reducethe dosage. The exact dosage will depend upon the mode ofadministration, on the therapy desired, form in which administered, thesubject to be treated and the body weight of the subject to be treated,and the preference and experience of the physician or veterinarian incharge.

Generally, the compounds of the invention are dispensed in unit dosageform comprising from about 0.05 to about 1000 mg of active ingredienttogether with a pharmaceutically acceptable carrier per unit dosage.

Usually, dosage forms suitable for oral, nasal, pulmonal or transdermaladministration comprise from about 0.05 mg to about 1000 mg, preferablyfrom about 0.5 mg to about 250 mg of the compounds admixed with apharmaceutically acceptable carrier or diluent.

The invention also encompasses prodrugs of a compound of the inventionwhich on administration undergo chemical conversion by metabolicprocesses before becoming active pharmacological substances. In general,such prodrugs will be functional derivatives of a compound of theinvention which are readily convertible in vivo into a compound of theinvention. Conventional procedures for the selection and preparation ofsuitable prodrug derivatives are described, for example, in “Design ofProdrugs”, ed. H. Bundgaard, Elsevier, 1985.

The invention also encompasses active metabolites of a compound of theinvention.

Thus, another aspect of the invention provides pharmaceuticalcompositions of the compounds of the invention, alone or in combinationwith another type antidiabetic agent and/or other type therapeuticagent.

In one example, the embodiments of the invention are represented by:

Pharmaceutical compositions comprising, as an active ingredient, atleast one compound of the invention which inhibits the enzymaticactivity of DPP-IV or a pharmaceutically acceptable salt or prodrug orhydrate thereof together with a pharmaceutically acceptable carrier ordiluent;

Pharmaceutical compositions comprising a compound of the invention asdescribed herein, in free form or in pharmaceutically acceptable acidaddition salt form, together with at least one pharmaceuticallyacceptable carrier or diluent;

Pharmaceutical compositions comprising a compound of formula VA, VB, ora mixture thereof and a pharmaceutically acceptable carrier or diluent;

Pharmaceutical compositions comprising:

a. a substantially pure preparation of a compound of formula VB asdescribed herein; and

b. a pharmaceutically acceptable carrier or diluent;

Methods of making a pharmaceutical composition comprising mixing asubstantially pure preparation of a compound of formula VB with apharmaceutically acceptable carrier or diluent;

Methods of making a pharmaceutical composition of a compound describedherein wherein the pharmaceutically acceptable carrier or diluent issuitable for oral administration;

Methods of making a pharmaceutical composition of a compound describedherein suitable for for oral administration further comprising the stepof formulating the composition into a tablet or capsule;

Methods of making a pharmaceutical composition of a compound describedherein wherein the pharmaceutically acceptable carrier or diluent issuitable for parenteral administration;

Methods of making a pharmaceutical composition of a compound describedherein suitable for parenteral administration further comprising thestep of lyophilizing the composition to form a lyophilized preparation;

Pharmaceutical compositions for the treatment, prevention or control ofatherosclerosis, comprising: (1) a compound of the invention, (2) anHMG-CoA reductase inhibitor, and (3) a pharmaceutically acceptablecarrier;

Pharmaceutical compositions, comprising:

a) A compound of the invention;

b) One or more compounds selected from the group consisting of:

-   -   i) Other dipeptidyl peptidase-IV inhibitors;    -   ii) Insulin sensitizers selected from the group consisting        of (i) PPAR agonists, (ii) biguanides, and (iii) protein        phosphatase-1B inhibitors;    -   iii) Insulin or insulin mimetics;    -   iv) Sulfonylureas or other insulin secretagogues;    -   v) α-glucosidase inhibitors;    -   vi) glucagons receptor agonists;    -   vii) GLP-1, GLP-1 mimetics, and GLP-1 receptor agonists;    -   viii) GIP, GIP mimetics, and GIP receptor agonists;    -   ix) PACAP, PACAP mimetics, and PACAP receptor 3 agonists;    -   x) GLP-2, GLP-2 mimetics, and GLP-2 receptor agonists;    -   xi) Cholesterol lowering agents selected from the group        consisting of (i) HMG-CoA reductase inhibitors, (ii)        sequestrants, (iii) nicotinyl alcohol, nicotinic acid or a salt        thereof, (iv) PPARα agonists, (v) PPARα/γ dual agonists, (vi)        inhibitors of cholesterol absorption, (vii) acyl CoA:cholesterol        acyltransferase inhibitors, and (viii) anti-oxidants;    -   xii) PPARδ agonists;    -   xiii) Anti-obesity compounds;    -   xiv) An ileal bile acid transporter inhibitor;    -   xv) Anti-inflammatory agents;    -   xvi) G-CSF, G-CSF mimetics, and G-CSF receptor agonists;    -   xvii) EPO, EPO mimetics, and EPO receptor agonists; and

c) a pharmaceutically acceptable carrier.

Pharmaceutical combinations comprising a compound of the invention, anantidiabetic agent other than a DPP-IV inhibitor for treating diabetesand related diseases, and an anti-obesity agent or a lipid-modulatingagent or both.

Pharmaceutical combinations comprising a compound of the invention andan antidiabetic agent;

Pharmaceutical combinations comprising a compound of the invention andan antidiabetic agent wherein the antidiabetic agent is 1, 2, 3 or moreof a biguanide, a sulfonyl urea, a glucosidase inhibitor, a PPAR γagonist, a PPAR α/γ dual agonist, an SGLT2 inhibitor, an aP2 inhibitor,a glycogen phosphorylase inhibitor, an AGE inhibitor, an insulinsensitizer, a glucagon-like peptide-1 (GLP-1) or mimetic thereof,insulin and/or a meglitinide;

Pharmaceutical combinations comprising a compound of the invention andan antidiabetic agent wherein the antidiabetic agent is 1, 2, 3 or moreof metformin, glyburide, glimepiride, glipyride, glipizide,chlorpropamide, gliclazide, acarbose, miglitol, pioglitazone,troglitazone, rosiglitazone, insulin, G1 -262570, isaglitazone, JTT-501,NN-2344, L895645, YM-440, R-119702, AJ9677, repaglinide, nateglinide,KAD1129, APR-HO39242, GW-409544, KRP297, AC2993, Exendin-4, LY307161,NN2211, and/or LY315902;

Pharmaceutical combinations comprising a compound of the invention andan antidiabetic agent wherein the compound is present in a weight ratioto the antidiabetic agent within the range from about 0.01 to about100:1;

Pharmaceutical combinations comprising a compound of the invention andan antidiabetic agent wherein the anti-obesity agent is a beta 3adrenergic agonist, a lipase inhibitor, a serotonin (and dopamine)reuptake inhibitor, a thyroid receptor beta compound, an anorecticagent, and/or a fatty acid oxidation upregulator;

Pharmaceutical combinations comprising a compound of the invention andan anti-obesity agent wherein the anti-obesity agent is orlistat,ATL-962, AJ9677, L750355, CP331648, sibutramine, topiramate, axokine,dexamphetamine, phentermine, phenylpropanolamine, famoxin, and/ormazindol;

Pharmaceutical combinations comprising a compound of the invention and alipid-modulating agent wherein the lipid-modulating agent is an MTPinhibitor, an HMG CoA reductase inhibitor, a squalene synthetaseinhibitor, a fibric acid derivative, an upregulator of LDL receptoractivity, a lipoxygenase inhibitor, an ACAT inhibitor, a cholesterylester transfer protein inhibitor, or an ATP citrate lyase inhibitor;

Pharmaceutical combinations comprising a compound of the invention and alipid-modulating agent wherein the lipid-modulating agent ispravastatin, lovastatin, simvastatin, atorvastatin, cerivastatin,fluvastatin, nisvastatin, visastatin, fenofibrate, gemfibrozil,clofibrate, implitapide, CP-529,414, avasimibe, TS-962, MD-700, and/orLY295427;

Pharmaceutical combinations comprising a compound of the invention and alipid-modulating agent wherein the compound is present in a weight ratioto the lipid-modulating agent within the range from about 0.01 to about100:1;

Pharmaceutical combinations comprising a compound of the invention andan agent for treating infertility, an agent for treating polycysticovary syndrome, an agent for treating a growth disorder and/or frailty,an anti-arthritis agent, an agent for preventing inhibiting allograftrejection in transplantation, an agent for treating autoimmune disease,an anti-AIDS agent, an agent for treating inflammatory boweldisease/syndrome, an agent for treating anorexia nervosa, ananti-osteoporosis agent and/or an anti-obesity agent.

Methods For Measuring Activity

The following methods were used to measure the activities of thecompounds of the invention which inhibit the enzymatic activity ofDPP-IV. The compounds of the invention are tested for their ability toinhibit the enzyme activity of purified DPP-IV. Briefly, the activity ofDPP-IV is measured in vitro by its ability to cleave the syntheticsubstrate Gly-Pro-p-nitroanilide (Gly-Pro-pNA). Cleavage of Gly-Pro-pNAby DPP-IV liberates the product p-nitroanilide (pNA), whose rate ofappearance is directly proportional to the enzyme activity. Inhibitionof the enzyme activity by specific enzyme inhibitors slows down thegeneration of pNA. Stronger interaction between an inhibitor and theenzyme results in a slower rate of generation of pNA. Thus, the degreeof inhibition of the rate of accumulation of pNA is a direct measure ofthe strength of enzyme inhibition. The accumulation of pNA is measuredspectrophotometrically. The inhibition constant, Ki, for each compoundis determined by incubating fixed amounts of enzyme with severaldifferent concentrations of inhibitor and substrate.

Thus, DPP-IV enzyme activity was determined by a fluorometric assay withthe substrate Gly-Pro-AMC which is cleaved by DPP-IV to release thefluorescent AMC leaving group. Free AMC (7-amino-4-methyl coumarin) wasmeasured using an excitation wavelength of 380 nm and an emissionwavelength of 460 nm with a Victor-II fluorescent reader. Stocksolutions of DPP-IV (1 ng/μl, pH 8.0) and Gly-Pro-AMC substrate (400 μM)in 25 mM Tris buffer (pH 8.0) were prepared separately. Test compoundswere dissolved in DMSO or in 50 mM glycine buffer (pH 3.0). The assaywas performed by diluting the DPP-IV stock (10 μl) into 25 mM Trisbuffer (77.5 μl) followed by addition of test compound (2.5 μl) at 26°C. After 10-minutes substrate was added (10 μl) and allowed to react for20-minutes at 26° C. before free AMC was measured. IC₅₀ values weredetermined in triplicate, using a minimum of six different inhibitorconcentrations. IC₅₀ values were calculated using Nonlinear RegressionAnalysis (GraphPad, Prism, San Diego, Calif.).

To determine the DPP-IV activity in the plasma of mice dosed with testcompounds, plasma (10 μl) was diluted into 25 mM Tris buffer (80 μl, pH8.0) followed by addition of Gly-Pro-AMC stock solution (10 μl) and thefree AMC measured after 20-minutes at 26° C. Analysis was performed asdescribed above.

The Zucker Diabetic Fatty (ZDF) rat model can be used to investigate theeffects of the compounds of the invention on both the treatment andprevention of diabetes as rats of this sub-strain are initiallypre-diabetic although they develop severe type 2 diabetes characterizedby increased HbA1 c levels over a period of 6 weeks. The same strain canbe used to predict the clinical efficacy of other anti-diabetic drugtypes. For example, the model predicts the potency and limited clinicalefficacy of thiazolidinedione insulin sensitizer compounds.

The purification of porcine DPP-IV and the enzyme assay under steadystate conditions are described in (1) Rahfeld, J. Schutkowski, M.,Faust, J., Neubert., Barth, A., and Heins, J. (1991) Biol. Chem.Hoppe-Seyler, 372, 313-318; and (2) Nagatsu, T., Hino, M., Fuyamada, H.,Hayakawa, T., Sakakibara, S., Nakagawa, Y., and Takemoto, T. (1976)Anal. Biochem., 74, 466-476, respectively.

Definitions

The term “DPP-IV” denotes dipeptidyl peptidase IV (EC 3.4.14.5; DPP-IV),also known as “CD-26.” DPP-IV cleaves a dipeptide from the N terminus ofa polypeptide chain containing a proline or alanine residue in thepenultimate position.

The term “diabetes and related diseases” refers to Type II diabetes,Type I diabetes, impaired glucose tolerance, obesity, hyperglycemia,Syndrome X, dysmetabolic syndrome, diabetic complications, diabeticdyslipidemia, hyperinsulinemia, and the like.

The conditions, diseases and maladies collectively referred to as“diabetic complications” include retinopathy, neuropathy andnephropathy, and other known complications of diabetes.

The term “other type(s) of therapeutic agents” as employed herein refersto one or more antidiabetic agents (other than DPP-IV inhibitors of theinvention), one or more anti-obesity agents, and/or one or morelipid-modulating agents (including anti-atherosclerosis agents), and/orone or more infertility agents, one or more agents for treatingpolycystic ovary syndrome, one or more agents for treating growthdisorders, one or more agents for treating frailty, one or more agentsfor treating arthritis, one or more agents for preventing allograftrejection in transplantation, one or more agents for treating autoimmunediseases, one or more anti-AIDS agents, one or more anti-osteoporosisagents, one or more agents for treating immunomodulatory diseases, oneor more agents for treating chronic inflammatory bowel disease orsyndrome and/or one or more agents for treating anorexia nervosa.

The term “lipid-modulating” agent as employed herein refers to agentswhich lower LDL and/or raise HDL and/or lower triglycerides and/or lowertotal cholesterol and/or other known mechanisms for therapeuticallytreating lipid disorders.

The term “treatment” is defined as the management and care of a patientfor the purpose of combating the disease, condition, or disorder andincludes administering a compound of the present invention to preventthe onset of the symptoms or complications, or alleviating the symptomsor complications, or eliminating the disease, condition, or disorder.

The term “beta cell degeneration” is intended to mean loss of beta cellfunction, beta cell dysfunction, and death of beta cells, such asnecrosis or apoptosis of beta cells.

By “substantially pure” in relation to compounds of the invention suchas, but not limited to, those of formula VA and VB, it is meant that oneisomer or the other, including all enantiomers, diastereoisomers,solvates, hydrates, and pharmaceutically acceptable salts thereof,represents at least 90% by weight of the composition. In someembodiments one isomer represents at least 98% by weight of thecomposition.

The term “boronic acid protecting group” as used herein refers to amoiety employed to block or protect the boronic acid functionality whilereactions involving other functional sites of the compound are carriedout. Typically, the boronic acid OH groups are protected as boronic acidesters derived from alchohols such as (+)-pinanediol; pinacol;1,2-dicyclohexyl-ethanediol; 1,2-ethanediol; 2,2-diethanolamine;1,3-propanediol; 2,3-butanediol, diisopropyl tartrate; 1,4-butanediol;diisopropylethanediol; (S,S,)-5,6-decanediol;1,1,2-triphenyl-1,2-ethanediol;(2R,3R)-1,4-dimethyoxy-1,1,4,4-tetraphenyl-2,3-butanediol; methanol;ethanol; isopropanol; catechol; 1-butanol; and the like. As will beunderstood by those skilled in the art, alcohols having only a singlehydroxy group, such as methanol, form diesters having the structure—B(OR)₂ in which R is the organic moiety from the alcohol (e.g.,—B(OMe)₂). By comparison, diols such as pinacol form cyclic boronicdiesters with —B(OH)₂ in which the organic moiety (e.g.,—C(Me)₂-C(Me)₂-)is attached to both oxygens.

The term “N-protecting group” or “N-protected” as used herein refers tothose groups intended to protect the N-terminus of an amino acid orpeptide or to protect an amino group against undesirable reactionsduring synthetic procedures. Commonly used N-protecting groups aredisclosed in T. W. Greene, P. G. Wuts, “Protective Groups In OrganicSynthesis, 3^(rd) Ed.” (John Wiley & Sons, New York (1999)), which ishereby incorporated by reference. N-protecting groups comprise acylgroups such as formyl, acetyl, propionyl, pivaloyl, t-butylacetyl,2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl,phthalyl, o-nitrophenoxyacetyl, α-chlorobutyryl, benzoyl,4-chlorobenzoyl, 4-bromobenzoyl, 4-nitrobenzoyl, and the like; sulfonylgroups such as benzenesulfonyl, p-toluenesulfonyl and the like;carbamate forming groups such as benzyloxycarbonyl,p-chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl,p-nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl,p-bromobenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl,3,5-dimethoxybenzyloxycarbonyl, 2,4-dimethoxybenzyloxycarbonyl,4-methoxybenzyloxycarbonyl, 2-nitro-4,5-dimethoxybenzyloxycarbonyl,3,4,5-trimethoxybenzyloxycarbonyl,1-(p-biphenylyl)-1-methylethoxycarbonyl, α,α-dimethyl-3,5-dimethoxybenzyloxycarbonyl, benzhydryloxycarbonyl,t-butyloxycarbonyl, diisopropylmethoxycarbonyl, isopropyloxycarbonyl,ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl,2,2,2,-trichloroethoxycarbonyl, phenoxycarbonyl, 4-nitrophenoxycarbonyl,fluorenyl-9-methoxycarbonyl, cyclopentyloxycarbonyl,adamantyloxycarbonyl, cyclohexyloxycarbonyl, phenylthiocarbonyl and thelike; alkyl groups such as benzyl, triphenylmethyl, benzyloxymethyl andthe like; and silyl groups such as trimethylsilyl and the like.Preferred N-protecting groups are formyl, acetyl, benzoyl, pivaloyl,t-butyl acetyl, phenylsulfonyl, benzyl, 9-fluorenylmethyloxycarbonyl(Fmoc), t-butyloxycarbonyl (Boc) and benzyloxycarbonyl (Cbz).

The term “alkyl” or “(C₁₋₁₂)alkyl”, alone or in combination, refers tolinear or branched chains and may include cyclic portions, having from1-12 (the use of 1-12 herein implies each of 1, 2, 3, 4, 5, 6, 7, 8, 9,10, 11 and 12) carbon atoms, such as but not limited to, e.g. methyl,ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl,n-pentyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 4-methylpentyl,neopentyl, 2,2-dimethylpropyl, and the like.

The terms “(C₁₋₁₀)alkyl”, “(C₁₋₈)alkyl” and “(C₁₋₆)alkyl”, alone or incombination, refers to linear or branched chains and may include cyclicportions, having from 1-10, 1-8, or 1-6 carbon atoms, respectively, suchas but not limited to, e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl,sec-butyl, isobutyl, tert-butyl, n-pentyl, 2-methylbutyl, 3-methylbutyl,n-hexyl, 4-methylpentyl, neopentyl, 2,2-dimethylpropyl, and the like.

The term “(C₁₋₄)alkyl”, alone or in combination, refers to linear orbranched chains and may include cyclic portions, having from 1-4 carbonatoms, such as but not limited to, e.g. methyl, ethyl, n-propyl,isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, and the like.

The terms “(C₂₋₁₂)alkenyl” and “(C₂₋₁₀)alkenyl”, alone or incombination, refers to a straight or branched, unsaturated hydrocarbonchain having from 2-12 or 2-10 carbon atoms, respectively, and at leastone double bond, such as, but not limited to, vinyl, 1-propenyl, allyl,isopropenyl, n-butenyl, n-pentenyl, n-hexenyl, and the like.

The terms “(C₂₋₁₂)alkynyl” and “(C₂₋₁₀)alkynyl”, alone or incombination, refers to an unsaturated hydrocarbon chain having from 2-12or 2-10 carbon atoms, respectively, and at least one triple bond, suchas but not limited to —C≡CH, —C≡C—CH₃, —CH₂C≡CH, —CH₂—CH₂—C≡CH,—CH(CH₃)C≡CH, and the like.

The terms “(C₃₋₁₂)cycloalkyl” and “(C₃₋₁₀)cycloalkyl” refers to one ormore saturated cyclic hydrocarbons having from 3-12 or 3-10 carbonatoms, respectively, such as, but not limited to, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, adamantyl, and the like.

The term “(C₅₋₁₀)cycloalkenyl” refers to a radical of one or more cyclichydrocarbon having at least one double bond having from 5-10 carbonatoms such as, but not limited to, cyclopentenyl, cyclohexenyl, and thelike.

The term “cycloalkylene” refers to a “cycloalkyl” group which has singlebonds for attachment at two different carbon atoms.

The terms “(C₁₋₆)alkylaminocarbonyl” and “di-(C₁₋₆)alkylaminocarbonyl”refer to straight or branched chain hydrocarbon groups having 1 to 6carbon atoms connected to NC(═O). Exemplary alkyl groups include but arenot limited to methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl,isobutyl, pentyl, hexyl, and the like.

The term “(C₁₋₆)alkylcarbonyl” refers to linear or branched chain andcyclic hydrocarbon groups having 1 to 6 carbon atoms connected to C(═O).Exemplary alkyl groups include but are not limited to methyl, ethyl,propyl, isopropyl, n-butyl, t-butyl, isobutyl, pentyl, hexyl, and thelike.

The term (C₃₋₈)cycloalkylcarbonyl refers to cyclic hydrocarbon groupshaving 3 to 8 carbon atoms connected to C(═O). Exemplary cycloalkylgroups include but are not limited to cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, and the like.

The terms “(C₁₋₁₀)alkoxy”, “(C₁₋₈)alkoxy” and “(C₁₋₆)alkoxy”, alone orin combination, refers to “O” connected to alkyl, having linear orbranched chains and may include cyclic portions, having from 1-10, 1-8or 1-6 carbon atoms, respectively. Examples of linear alkoxy groupsinclude but are not limited to methoxy, ethoxy, propoxy, butoxy,pentoxy, hexoxy, and the like. Examples of branched alkoxy include butare not limited to isoprpoxy, sec-butoxy, tert-butoxy, isopentoxy,isohexoxy, and the like. Examples of cyclic alkoxy include but are notlimited to cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy,and the like.

The term “aryloxy” refers to an aryl group bonded to O.

The term “alkanoyl”, alone or as part of another group, refers to alkyllinked to a carbonyl group.

The term “alkylene” refers to alkyl groups which have single bonds forattachment at two different carbon atoms.

The term “alkenylene” refers to alkenyl groups which have single bondsfor attachement at two different carbon atoms.

The terms “alkynylene” refers to alkynyl groups which have single bondsfor attachement at two different carbon atoms.

The term “aryl” refers to monocyclic, bicyclic, or tricyclic carbocyclicaromatic ring systems having 6 to 14 carbon atoms in the ring portion.Examples of aryl groups include but are not limited to phenyl, naphthyl,biphenyl, anthracenyl, azulenyl, and the like. Aryl is also intended toinclude the partially hydrogenated derivatives of the carbocyclicsystems including 1,2,3,4-tetrahydro-naphthyl, indanyl and the like.

The term “heteroaryl” as used herein includes heterocyclic unsaturatedring systems containing one or more heteroatoms selected from nitrogen,oxygen and sulphur. Examples of heteroaryl groups include but are notlimited to furyl, thienyl, pyrrolyl, and the like. Heteroaryl is alsointended to include the partially hydrogenated derivatives of theheterocyclic systems enumerated below.

Examples of “aryl” and “heteroaryl” includes but are not limited tophenyl, biphenyl, indenyl, naphthyl (1-naphthyl, 2-naphthyl),N-hydroxytetrazolyl, N-hydroxytriazolyl, N-hydroxyimidazolyl,anthracenyl (1-anthracenyl, 2-anthracenyl, 3-anthracenyl), thiophenyl(2-thienyl, 3-thienyl), furyl (2-furyl, 3-furyl), indolyl, oxadiazolyl,isoxazolyl, quinazolinyl, fluorenyl, xanthenyl, isoindanyl, benzhydryl,acridinyl, thiazolyl, pyrrolyl (2-pyrrolyl), pyrazolyl (3-pyrazolyl),imidazolyl (1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl),triazolyl (1,2,3-triazol-1-yl, 1,2,3-triazol-2-yl, 1,2,3-triazol-4-yl,1,2,4-triazol-3-yl), oxazolyl (2-oxazolyl, 4-oxazolyl, 5-oxazolyl),thiazolyl (2-thiazolyl, 4-thiazolyl, 5-thiazolyl), pyridyl (2-pyridyl,3-pyridyl, 4-pyridyl), pyrimidinyl (2-pyrimidinyl, 4-pyrimidinyl,5-pyrimidinyl, 6-pyrimidinyl), pyrazinyl, pyridazinyl (3-pyridazinyl,4-pyridazinyl, 5-pyridazinyl), quinolyl (2-quinolyl, 3-quinolyl,4-quinolyl, 5-quinolyl, 6-quinolyl, 7-quinolyl, 8-quinolyl), isoquinolyl(1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl,6-isoquinolyl, 7-isoquinolyl, 8-isoquinolyl), benzo[b]furanyl(2-benzo[b]furanyl, 3-benzo[b]furanyl, 4-benzo[b]furanyl,5-benzo[b]furanyl, 6-benzo[b]furanyl, 7-benzo[b]furanyl),2,3-dihydro-benzo[b]furanyl (2-(2,3-dihydro-benzo[b]furanyl),3-(2,3-dihydro-benzo[b]furanyl), 4-(2,3-dihydro-benzo[b]furanyl),5-(2,3-dihydro-benzo[b]furanyl), 6-(2,3-dihydro-benzo[b]furanyl),7-(2,3-dihydro-benzo[b]furanyl), benzo[b]thiophenyl(2-benzo[b]thiophenyl, 3-benzo[b]thiophenyl, 4-benzo[b]thiophenyl,5-benzo[b]thiophenyl, 6-benzo[b]thiophenyl, 7-benzo[b]thiophenyl),2,3-dihydro-benzo[b]thiophenyl, (2-(2,3-dihydro-benzo[b]thiophenyl),3-(2,3-dihydro-benzo[b]thiophenyl), 4-(2,3-dihydro-benzo[b]thiophenyl),5-(2,3-dihydro-benzo[b]thiophenyl), 6-(2,3-dihydro-benzo[b]thiophenyl),7-(2,3-dihydro-benzo[b]thiophenyl), indolyl (1-indolyl, 2-indolyl,3-indolyl, 4-indolyl, 5-indolyl, 6-indolyl, 7-indolyl), indazole(1-indazolyl, 3-indazolyl, 4-indazolyl, 5-indazolyl, 6-indazolyl,7-indazolyl), benzimidazolyl (1-benzimidazolyl, 2-benzimidazolyl,4-benzimidazolyl, 5-benzimidazolyl, 6-benzimidazolyl, 7-benzimidazolyl,8-benzimidazolyl), benzoxazolyl (1-benzoxazolyl, 2-benzoxazolyl),benzothiazolyl (1-benzothiazolyl, 2-benzothiazolyl, 4-benzothiazolyl,5-benzothiazolyl, 6-benzothiazolyl, 7-benzothiazolyl), carbazolyl(1-carbazolyl, 2-carbazolyl, 3-carbazolyl, 4-carbazolyl),5H-dibenz[b,f]azepine (5H-dibenz[b,f]azepin-1-yl,5H-dibenz[b,f]azepine-2-yl, 5H-dibenz[b,f]azepine-3-yl,5H-dibenz[b,f]azepine-4-yl, 5H-dibenz[b,f]azepine-5-yl),10,11-dihydro-5H-dibenz[b,f]azepine(10,11-dihydro-5H-dibenz[b,f]azepine-1-yl,10,11-dihydro-5H-dibenz[b,f]azepine-2-yl,10,11-dihydro-5H-dibenz[b,f]azepine-3-yl,10,11-dihydro-5H-dibenz[b,f]azepine-4-yl,10,11-dihydro-5H-dibenz[b,f]azepine-5-yl), and the like.

The terms “arylalkenyl” and “arylalkynyl” alone or as part of anothergroup refer to alkenyl and alkynyl groups as described above having anaryl substituent.

The terms “halogen” and “halo” refers to chloro, fluoro, bromo or iodo.

The term “alkylamino”, “arylamino”, or “arylalkylamino” alone or as partof another group includes any of the above alkyl, aryl or arylalkylgroups linked to a nitrogen atom.

The term “substituted amino” as employed herein alone or as part ofanother group refers to amino substituted with one or two substituents,which may be the same or different, such as alkyl, aryl, arylalkyl,heteroaryl, heteroarylalkyl, cycloheteroalkyl, cycloheteroalkylalkyl,cycloalkyl, cycloalkylalkyl haloalkyl, hydroxyalkyl, alkoxyalkyl orthioalkyl. These substituents may be further substituted with any of thegroups as set out above. In addition, the amino substituents may betaken together with the nitrogen atom to which they are attached to form1-pyrrolidinyl, 1-piperidinyl, 1-azepinyl, 4-morpholinyl,4-thiamorpholinyl, 1-piperazinyl, 4-alkyl-1-piperazinyl,4-arylalkyl-1-piperazinyl, 4-diarylalkyl-1-piperazinyl, 1-pyrrolidinyl,1-piperidinyl, or 1-azepinyl, optionally substituted with alkyl, alkoxy,alkylthio, halo, trifluoromethyl or hydroxy.

The terms “alkylthio”, “arylthio” or “aralkylthio” alone or as part ofanother group includes any of the above alkyl, aralkyl or aryl groupslinked to a sulfur atom.

The term “acyl” by itself or part of another group refers to an organicradical linked to a carbonyl group; examples of acyl groups include anyof the groups attached to a carbonyl, such as alkanoyl, alkenyl, aroyl,aralkanoyl, heteroaroyl, cycloalkanoyl, cycloheteroalkanoyl, and thelike.

The term “cycloheteroalkyl” alone or as part of another group refers toa 3-, 4-, 5-, 6- or 7-membered saturated or partially unsaturated ringwhich includes 1 to 2 hetero atoms such as nitrogen, oxygen and/orsulfur, linked through a carbon atom or a heteroatom, where possible,optionally via the linker (CH₂)_(g) (where g is 1, 2 or 3). The abovegroups may include 1 to 4 substituents such as alkyl, halo, oxo, and thelike. In addition, any of the cycloheteroalkyl rings can be fused to acycloalkyl, aryl, heteroaryl or cycloheteroalkyl ring.

The term “cycloheteroalkylalkyl” alone or as part of another grouprefers cycloheteroalkyl groups as defined above linked through a carbonatom or heteroatom to a (CH₂)_(r) chain.

The term “heteroarylalkyl” or “heteroarylalkenyl” alone or as part ofanother group refers to a heteroaryl group as defined above linkedthrough a C atom or heteroatom to a (CH₂)_(r) chain, alkylene oralkenylene as defined above.

The phrase “naturally occurring α-amino acid sidechain” refers to themoieties (sidechains) attached to the α-amino carbon in the followingnaturally occurring α-amino acids: glycine, alanine, 2-aminobutyricacid, valine, leucine, isoleucine, tert-leucine, serine, threonine,cysteine, asparagine, aspartic acid, glutamine, glutamic acid,phenylalanine, histidine, tryptophan, tyrosine, phenylglycine, lysine,methionine, and arginine. The side chains of these amino acids are wellknown in the art. For example, the α-amino acid sidechain of alanine ismethyl; the sidechain of phenylalanine is benzyl; and the sidechain oftert-leucine is tert-butyl.

The term “polyhaloalkyl” refers to an “alkyl” group as defined abovewhich includes from 2 to 9, preferably from 2 to 5, halo substituents,such as F or Cl, preferably F, such as CF₃CH₂, CF₃ or CF₃CF₂CH₂.

The term “polyhaloalkoxy” refers to an “alkoxy” or “alkyloxy” group asdefined above which includes from 2 to 9, preferably from 2 to 5, halosubstituents, such as F or Cl, preferably F, such as CF₃CH₂O, CF₃O orCF₃CF₂CH₂O.

The terms “polycyclic” and “polycycle” refer to two or more rings (e.g.,cycloalkyls, cycloalkenyls, aryls, heteroaryls and/or cycloheteroalkyls)in which two or more carbons are common to two adjoining rings, e.g.,the rings are “fused rings.” Fused rings that are joined throughnonadjacent atoms, are also known as “bridged” rings. Each of the ringsof the polycycle can be substituted with such substituents as describedabove, as for example, halogen, alkyl, aralkyl, alkenyl, alkynyl,cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido,phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio,sulfonyl, ketone, aldehyde, ester, a heterocyclyl, an aromatic orheteroaromatic moiety, trifluoromethyl, cyano, or the like.

Examples

A further detailed description of the invention is given with referenceto the following non-limiting examples.

Example 1 Synthesis of (2R)-boroPro-(1S,2S,3R,5S)-pinanediol ester,hydrochloride (2)

A flame dried round bottom flask equipped with a magnetic stir bar wascharged with N-Boc-pyrrolidine (20 g, 117 mmol, 1 eq) and dry THF (60mL) under a nitrogen atmosphere. The clear colorless solution was cooledto −78° C. and a solution of s-BuLi (100 mL of a 1.4 M solution incyclohexane, 140 mmol) was added slowly over a 30 minute period. Thelight orange colored solution was stirred at −78° C. for 3 hoursfollowed by treatment with B(OMe)₃ (39 mL, 350 mmol) after which thecooling bath was removed and the clear colorless solution slowly warmedto 0° C. Upon reaching 0° C., the reaction was quenched with a smallamount of water (˜2 mL), allowed to warm to room temp then extractedinto 2 N NaOH (250 mL) and backwashed with additional EtOAc (150 mL).The aqueous phase was acidified to pH 3 by the addition of 2 N HCl andthen extracted with EtOAc (3×120 mL). The organic extracts were combinedand dried over Na₂SO₄ and concentrated to produce the free boronic acid(22.08 g, 103 mmol) as a sticky white solid in 88% yield. Withoutfurther purification the boronic acid was dissolved in tert-butyl methylether (150 mL) and with constant stirring (+)-pinanediol (17.5 g, 103mmol) was added at room temperature. After 18 hr the ether was removedand the (+)-pinanediol boronic ester was purified by columnchromatography (silica gel, 1:3 hexanes/EtOAc) to give a clear thick oil(26.84 g, 76.8 mmol, 76% yield, R_(f)=0.6 using a 2:1 hexane/ethylacetate eluant, made visual via I₂ and/or PMA stain). Removal of the Bocprotecting group was achieved by dissolving the oil in dry ether,cooling to 0° C. in an ice bath and with constant stirring dry HCI (g)was bubbled into the solution for 10 minutes. After 2 hours a whiteprecipitate developed in the flask and the ether and excess HCl wereremoved in vacuo to afford the racemic HCl salt as a white solid.Crystallization and isolation of the desired isomer was performed bydissolving the HCl salt in a minimal amount of dichloromethane (250 mL)with gentle heating to facilitate a homogenous solution followed bycontinuous stirring for 8 hours to yield a fluffy white precipitate thatwas collected by vacuum filtration, dried and then dissolved in minimal2-propanol (˜200 mL) with gentle heating until homogenous. The alcoholicsolution was stirred over night and the resulting white precipitate wascollected by vacuum filtration affording isomerically pure 1 as a whitesolid. (7.0 g, 27 mmol, 23% yield). ¹H NMR (400 MHz, D₂O) δ 4.28 (d,J=8.0 Hz, 1H), 3.06 (m, 3H), 2.18 (m, 1H), 1.96 (m, 2H), 1.78 (m, 3H),1.62 (m, 2H), 1.21 (s, 3H), 1.05 (m, 5H), 0.84 (d, J=12 Hz, 2H), 0.71(s, 2H), 0.62 (s, 3H).

Example 2 Synthesis Of Series A Compounds:(2R)-1-(2-Cyclopentylamino-acetyl)-boroPro-OH (4) Step 1:(2R)-1-(2-Chloroacetyl)-boroPro-(1S,2S,3R,5S)-pinanediol ester (3A)

To a solution of 2 (36.7 g, 129.3 mmol) dissolved in dry CH₂Cl₂ (200 mL)cooled to 0° C. was added chloroacetyl chloride (12.34 mL, 155.2 mmol)under a blanket of N₂. To this was slowly dripped 4-methylmorpholine(42.4 mL, 182 mmol) to give an almost clear light orange solution thatwas warmed to room temp. After 30 minutes the solution was cooled againto 0° C. and 200 mL of a 0.2 N solution of HCl was added and the organiclayers separated, dried and concentrated to give a dark red oil that wasa single spot by TLC (2:1 hex/EtOAc, R_(f)=0.22, made visual via I₂and/or PMA stain) and was used in the next step without furtherpurification. ¹H NMR (400 MHz, CDCl₃) δ0.80 (s, 3H), 1.25 (m, 1H), 1.26(s, 3H), 1.42 (s, 3H), 1.75-1.96 (m, 4H), 1.98-2.10 (m, 3H), 2.12-2.20(m, 1H), 2.29-2.35 (m, 1H), 3.12-3.16 (m, 1H), 3.47-3.53 (m, 1H),3.58-3.63 (m, 1H), 3.97-4.05 (q, 2H), 4.30-4.32 (d, 1H).

Step 2:(2R)-1-(2-Cyclopentylamino-acetyl)-boroPro-(1S,2S,3R,5S)-pinanediolester (3B)

Compound 3A was dissolved in dry THF (˜150 mL) followed by addition ofK₂CO₃ (35 g) and cooled to 0° C. before addition of cyclopentylamine(21.93 g, 258 mmol). The reaction mixture was then allowed to warm toroom temperature and stirred overnight. TLC indicated all startingmaterial was consumed. The mixture was filtered through a celite andsilica pad, washed with 5% MeOH in CH₂Cl₂ (200 mL) and concentrated toyield a sticky, light orange solid. The red sticky solid was dissolvedin CH₂Cl₂ (150 mL) followed by addition of Et₂O (˜200 mL) and thesolution was stirred overnight. The resulting milky white solution wasthen filtered and the precipitate was washed with cold EtOAc (2×60 mL)and hexane (2×50 mL) and dried to give 3B (28.92 g, 120.5 mmol) as afluffy white solid. The dark red mother liquor filtrate was concentratedand subjected to the previous recrystallization conditions to obtain asecond crop of 3B (6.17 g, 25.7 mmol) for a combined overall yield of 3B(35.09 g, 93.8 mmol) of 73% yield. R_(f)=0.45 (10% MeOH in CH₂Cl₂). ¹HNMR (400 MHz, CDCl₃) δ 4.18 (d, 1H), 3.95 (d, J=16 Hz, 1H), 3.6 (d, J=16Hz, 1H), 3.46 (m, 3H), 2.74 (m, 1H), 2.36 (m, 1H), 2.16 (m, 2H), 2.04(m, 4H), 1.90 (s, 1H), 1.74 (m, 6H), 1.61 (s, 1H), 1.46 (m, 2H), 1.34(s, 3H), 1.30 (s, 3H), 0.88 (s, 3H).

Step 3: (2R)-1-(2-Cyclopentylamino-acetyl)-boroPro-OH (4)

To a solution of 3B (40.59 g, 108.5 mmol) in H₂O (200 mL, adjusted to pH2 by addition of 2 N HCl) was added hexane (200 mL) and phenyl boronicacid (13.37 g, 109.5 mmol) and the bi-phasic mixture was stirredvigorously. The hexane layer was periodically removed and replaced withfresh hexane 6 times over a 24-hour period. The aqueous layer wasseparated and applied to a Dowex 50-X2-100 ion exchange column (H+ form)and eluted with water until the eluate was neutral. Elution with aqueousammonium hydroxide (2 wt %) followed by lyophilization of theappropriate fractions yielded 4 (23.91 g, 99.6 mmol) as a whitecrystalline solid in a 92% yield. 4.TFA salt ¹H NMR (400 MHz, D₂O) δ3.88 (dd, J=8.0 Hz, 2H), 3.54 (m, 1H), 3.42 (m, 1H), 3.28 (m, 1H), 2.96(m, 1H), 1.96 (m, 4H), 1.85 (m, 2H), 1.63 (m, 7H); MS (ESI) m/z 223(M+H—H₂O)⁺.

Example 3 Synthesis of1-(2-Cyclopropylamino-acetyl)-pyrrolidine-(2R)-boronic acid. (A2)

The title compound was prepared according to the procedure of Example 2using appropriate starting materials. ¹H NMR (D₂O) δ 4.08 (dd, J=12 Hz,2H), 3.54 (m, 1H), 3.38 (m, 1H), 3.07 (m, 1H), 2.26 (m, 1H), 2.09 (m,2H), 1.94 (m, 1H), 1.71 (m, 1H), 0.88 (s, 4H); MS (ESI) m/z 195.13(MH⁺—H₂O).

Example 4 Synthesis of1-[2-(3-Hydroxy-adamantan-1-ylamino)-acetyl]-pyrrolidine-(2R)-boronicacid (A3)

The title compound was prepared according to the procedure of Example 2using appropriate starting materials. ¹H NMR (D₂O) δ 3.94 (d, J=8 Hz,2H), 3.54 (m, 1H), 3.40 (m, 1H), 3.09 (m, 1H), 2.41 (s, 2H), 2.09 (m,3H), 1.93 (m, 2H), 1.87 (m, 7H), 1.71 (m, 6H), 1.56 (m, 2H); MS (ESI)m/z 305.21 (MH⁺—H₂O).

Example 5 Synthesis of1-(5R-Phenyl-pyrrolidine-2S-carbonyl)-pyrrolidine-(2R)-boronic acid (6)Step 1: N-Boc-5-phenylPro-(2R)-boroPro-(1S,2S,3R,5S)-pinanediol ester(5)

To an ice-cooled (0° C.) solution of N-Boc-5-phenyl-Pro-OH (0.84 mmol)in dry CH₂Cl₂ was added EDAC (174 mg, 0.91 mmol) and HOBt (105 mg, 0.775mmol). The reaction was stirred at 0° C. for 15-minutes and then 2 (200mg, 0.7 mmol) and N-methyl morphiline (0.25 mL, 2.1 mmol) was added andthe reaction was slowly warmed to room temperature and the reactioncontinued for 8 hours. The coupling reaction was then quenched with theaddition of NaHCO₃ (10 mL), extracted into EtOAc (2×15 mL), washed withbrine (15 mL), dried over Na₂SO₄, concentrated and further purified viacolumn chromatography (silica gel, eluted with a gradient of EtOAc inhexanes, 30-50%) to afford 5 (320 mg, 0.62 mmol, 88%) as an off-whitesolid.

Step 2: 1-(5R-Phenyl-pyrrolidine-2S-carbonyl)-pyrrolidine-(2R)-boronicacid (6)

An ice-cooled solution of 5 (320 mg, 0.62 mmol) in dry ether wassaturated with dry HCl (g) and allowed to stir for 1-hour. The solutionwas then concentrated under vacuum to afford a sticky white solid thatwas taken up in H₂O (10 mL, adjusted to pH 2 by addition of 2 N HCl) andhexane (10 mL) and phenyl boronic acid (74 mg, 0.62 mmol) and thebi-phasic mixture was stirred vigorously. The hexane layer wasperiodically removed and replaced with fresh hexane 6 times over a24-hour period. The aqueous layer was separated and applied to a Dowex50-X2-100 ion exchange column (H⁺ form) and eluted with water until theeluate was neutral. Elution was continued with aqueous ammoniumhydroxide (2 wt %) and the appropriate fractions were lyophilized toafford the free boronic acid B1 (76 mg, 0.26 mmol) as an amorphous whitesolid. ¹H NMR (D₂O) δ 7.46 (m, 5H), 3.65 (m, 1H), 3.44 (m, 1H), 3.04 (m,1H), 2.54 (m, 1H), 2.38 (m, 2H), 2.20 (m, 1H), 2.06 (m, 2H), 1.86 (m,1H), 1.66 (m, 1H); MS (ESI) m/z 271 (MH⁺—H₂O).

Example 6 Synthesis of1-(Piperidine-2S-carbonyl)-pyrrolidin-(2R)-boronic acid (B2)

The title compound was prepared according to the procedure of Example 5using appropriate starting materials. ¹H NMR (D₂O) δ 4.07 (m, 1H), 3.61(m, 1H), 3.34 (m, 2H), 2.94 (m, 2H), 2.16 (m, 1H), 2.03 (m, 2H), 1.87(m, 3H), 1.56 (m, 4H); MS (ESI) m/z 209 (MH⁺—H₂O).

Example 8 Synthesis of1-(2,3-Dihydro-1H-indole-2S-carbonyl)-pyrrolidine-(2R)-boronic acid (B3)

The title compound was prepared according to the procedure of Example 5using appropriate starting materials. ¹H NMR (D₂O) δ 4.54 (m, 1H), 3.73(m, 1H), 3.58 (m, 1H), 3.34 (m, 1H), 2.48 (m, 1H), 2.37 (m, 1H), 2.06(m, 3H), 1.83 (m, 3H), 1.58 (m, 4H), 1.32 (m, 4H); MS (ESI) m/z 249(MH⁺—H₂O).

Example 9 Synthesis of1-(4S-Phenyl-pyrrolidine-2S-carbonyl)-pyrrolidine-(2R)-boronic acid (B4)

The title compound was prepared according to the procedure of Example 5using appropriate starting materials. ¹H NMR (D₂O) δ 7.34 (d, J=13 Hz,2H), 7.27 (m, 3H), 4.79 (m, 1H), 3.83 (m, 1H),3.59 (m, 1H), 3.34 (m,2H), 3.06 (m, 1H), 2.53 (m, 2H), 2.08 (m, 2H) 1.77 (m, 1H), 1.64 (m,1H); MS (ESI) m/z 271 (MH⁺—H₂O).

Example 10 Synthesis of(2R)-1-{2-[(3S)-Pyrrolidin-3-ylamino]-acetyl}-pyrrolidine-2-boronic acid(8)

Step 1:(2R)-1-{2-[(3S)-1-tert-Butoxycarbonyl-pyrrolidin-3-ylamino]-acetyl}-pyrrolidine-2-boronicacid (1S,2S,3R,5S)-pinanediol ester (7)

The protocol described above for the synthesis of 3B was followedemploying (35)-3-amino-pyrrolidine-1-carboxylic acid tert-butyl ester inplace of cyclopentylamine. Compound 7 was obtained as an oil.

(2R)-1-{2-[(3S)-Pyrrolidin-3-ylamino]-acetyl}-pyrrolidine-2-boronic acid(8)

The protocol described above for the deprotection of the pinanediolboronic ester 3B (Example 2, Step 3) was applied to 7. Compound 8 wasobtained as a white solid. 8.TFA salt. ¹H-NMR (500 MHz, CD₃OD) δ 4.12(m, 3H), 3.76 (m, 1H), 3.54 (m, 3H), 3.41 (m, 2H), 3.26 (m, 1H), 2.55(m, 1H), 2.28 (m, 1H), 2.05 (m, 3H), 1.74 (m, 1H). MS m/z (relintensity) 241 (M) (27), 224 (100), 209 (73), 155 (47).

Example 11 Synthesis of(2R)-1-{2-[(3R)-Pyrrolidin-3-ylamino]-acetyl}-pyrrolidine-2-boronic acid(10)

Step 1:(2R)-1-{2-[(3R)-1-tert-Butoxycarbonyl-pyrrolidin-3-ylamino]-acetyl}-pyrrolidine-2-boronicacid (1S,2S,3R,5S)-pinanediol ester (9)

The protocol described above for the synthesis of 3B was followedemploying (3R)-3-amino-pyrrolidine-1-carboxylic acid tert-butyl ester inplace of cyclopentylamine. Compound 9 was obtained as an oil. MS m/z(rel intensity) 476 (M+1)⁺ (100), 376 (74), 239 (38), 224 (67), 155(55).

Step 2:(2R)-1-{2-[(3R)-Pyrrolidin-3-ylamino]-acetyl}-pyrrolidine-2-boronic acid(10)

The protocol described above for the deprotection of the pinanediolboronic ester 3B (Example 2, Step 3) was applied to 9. Compound 10 wasobtained as a white solid. 10-TFA salt. ¹H-NMR (500 MHz, CD₃OD) δ 4.13(m, 1H), 4.08 (bs, 2H), 3.76 (dd, J=13.0, 8.0 Hz, 1H), 3.55 (m, 3H),3.41 (m, 2H), 3.27 (m, 1H), 2.53 (m, 1H), 2.26 (m, 1H), 2.10 (m, 2H),1.99 (m, 1H), 1.75 (m, 1H). MS m/z (rel intensity) 224 (M−17) (100), 206(25), 180 (29), 155 (70).

Example 12 Synthesis of Series B Compounds:(2R)-1-[(2S)-Azetidine-2-carbonyl]-boroPro-OH (12) Step 1:(2R)-1-[(2S)-1-tert-Butoxycarbonyl-azetidine-2-carbonyl]-boroPro-(1S,2S,3R,5S)-pinanediolester (11)

To a solution of (2S)-azetidine-1,2-dicarboxylic acid 1-tert-butyl ester(169 mg, 0.8 mmol) in CH₂Cl₂ (5 mL) was added HOBt (105 mg, 0.8 mmol)and EDC (174 mg, 0.9 mmol). The reaction solution was then cooled to 0°C. in an ice bath for 10 min followed by sequential addition of 2 (200mg, 0.7 mmol) and NMM (0.25 mL, 2.1 mmol). The reaction solution wasallowed to warm up to room temperature and stirred overnight. Thereaction mixture was diluted with additional CH₂Cl₂ (5 mL), washed withNaHCO₃ (2×10 mL), 0.1 M aqueous HCl (5 mL) and brine (10 mL). Theorganic layer was dried over Na₂SO₄ and evaporated under reducedpressure. The resulting oily residue was purified by columnchromatography (silica gel, solvent eluent gradient from 1:4EtOAc/hexane to 1:2 EtOAc/hexane) to afford 11 as a clear viscous oil.

Step 2: (2R)-1-[(2S)-Azetidine-2-carbonyl]-boroPro-OH (12)

A solution of compound 11 in 4N HCl in dioxane was stirred at roomtemperature for 4 h. The solvent was removed under vacuum and theresulting residue was submitted to the pinanediol ester deprotectionprotocol described above for the preparation of boronic acid 4. Compound12 was obtained as a white solid. 12-TFA salt ¹H-NMR (500 MHz, D₂O) δ5.23 (m, 1H), 4.11 (m, 1H), 3.90 (m, 1H), 3.42 (m, 1H), 3.18 (m, 1H),2.99 (m, 1H), 2.79 (m, 1H), 2.55 (m, 1H), 1.92 (m, 3H), 1.63 (m, 1H). MSm/z (rel intensity) 199 (M+1)⁺ (7), 181 (M−17) (100), 152 (53).

Example 13 Synthesis of Series C Compounds:(2R)-1-[(2S,4S)-4-Amino-pyrrolidine-2-carbonyl]-boroPro-OH (15) Step 1:(2R)-1-[(2S,4S)-1-tert-Butoxycarbonyl-4-benzyloxycarbonylamino-pyrrolidine-2-carbonyl]-boroPro-(1S,2S,3R,5S)-pinanediolester (13)

The protocol described for the synthesis of 11 was followed employing(2S,4S)-Fmoc-4-amino-1-boc-pyrrolidine-2-carboxylic acid (628 mg, 2.2mmol) in place of azetidine-1,2-dicarboxylic acid 1-tert-butyl ester.Compound 13 was obtained as a clear colorless oil that was used in thenext step without further purification.

Step 2:(2R)-1-[(2S,4S)-1-tert-Butoxycarbonyl-4-amino-pyrrolidine-2-carbonyl]-boroPro-(1S,2S,3R,5S)-pinanediolester (14)

To a solution of 13 dissolved in DCM (10 ml) was added diethyl amine (5ml) at once and the resulting colorless solution was stirred overnightat room temperature. The reaction was evaporated to dryness andadditional DCM was added followed by evaporation once again to dryness.The resulting oil was purified by column chromatography (silica gel,eluted with a gradient of 2.5 to 5% MeOH in DCM, made visible by I₂and/or PMA) to give 14 as a clear colorless oil in a 48% yield over 2steps.

Step 3: (2R)-1-[(2S,4S)-4-Amino-pyrrolidine-2-carbonyl]-boroPro-OH (15)

The protocol described above for the N-Boc deprotection and pinanediolester hydrolysis in the synthesis of compound 12 was applied to 14.Compound 15 was obtained as a white solid. 15.TFA salt ¹H-NMR (500 MHz,D₂O) δ 4.42 (dd, 1H), 3.87 (m, 1H), 3.5 (dd, 1H), 3.28 (m, 2H), 3.07 (m,1H), 2.73 (m, 1H), 2.64 (m, 1H), 1.86 (m, 1H), 1.72 (br m, 2H), 1.55 (brm, 2H), 1.34 (m, 2H). MS m/z (rel intensity) 228 (M+1) (55), 210(M+1-H₂O) (95).

Example 14 Synthesis of Series D Compounds:(2R)-1-[(2S)-4-Methanesulfonyl-piperazine-2-carbonyl]-boroPro-OH (19)Step 1:(2R)-1-[(2S)-1-tert-Butoxycarbonyl-4-benzyloxycarbonyl-piperazine-2-carbonyl]-boroPro-(1S,2S,3R,5S)-pinanediolester (16)

The protocol described above for the synthesis of 11 was followedemploying (25)-N-1-Boc-N-4-Cbz-2-piperazine carboxylic acid (1 g, 2.6mmol) in place of azetidine-1,2-dicarboxylic acid 1-tert-butyl ester.Compound 16 (690 mg, 1.5 mmol) was obtained in 57% yield as an oil aftersilica gel column chormatography. MS m/z (rel intensity) 618 (M+23)⁺(17), 596 (M+1)⁺ (100), 496 (38).

Step 2:(2R)-1-[(2S)-1-tert-Butoxycarbonyl-piperazine-2-carbonyl]-boroPro-(1S,2S,3R,5S)-pinanediolester (17)

To a solution of compound 16 (314 mg, 0.53 mmol) in MeOH (6 mL) wasadded Pd/C (40 mg). The mixture was stirred under a H₂ atmosphere for 2h. Upon completion of the reaction, it was filtered through a plough ofCelite. The solvents were removed under reduced pressure and the oilyresidue used in the next step without further purification. MS m/z (relintensity) 462 (M+1)⁺ (100), 406 (12), 362 (11).

Step 3:(2R)-1-[(2S)-1-tert-Butoxycarbonyl-4-methanesulfonyl-piperazine-2-carbonyl]-boroPro-(1S,2S,3R,5S)-pinanediolester (18)

To a solution of compound 17 (214mg, 0.46 mmol) in CH₂Cl₂ (5 mL) cooledto 0° C. was sequentially added N-methylmorpholine (204 μL, 1.9 mmol)and methanesulfonyl chloride (72 μL, 0.93 mmol). The reaction mixturewas allowed to warm up to room temperature and stir for 3 hours. Thereaction was then diluted with CH₂Cl₂ (6 ml) and water (6 mL). Theorganic phase was isolated and dried over MgSO₄. After filtration,solvents were removed under reduced pressure. The oily residue waspurified by column chromatography (silica gel) using a mixture ofEtOAc/Hexanes as eluent. Compound 18 (112 mg, 0.21 mmol) was obtained in45% yield. MS m/z (rel intensity) 562 (M+23)⁺ (14), 540 (M+1) (100), 388(75).

Step 4: (2R)-1-[(2S)-4-Methanesulfonyl-piperazine-2-carbonyl]-boroPro-OH(19)

The protocol described above for the N-Boc deprotection and pinanediolester hydrolysis in the synthesis of compound 12 was applied to 18 (112mg, 0.21 mg). Compound 19 (32 mg, 0.11 mmol) was obtained in 53% yield.19.TFA salt ¹H-NMR (500 MHz, D₂O) δ 4.32 (dd, J=11.0, 3.5 Hz, 1H), 4.05(m, 1H), 3.93 (m, 1H), 3.77 (m, 1H), 3.60 (ddd, J=10.5, 8.0, 2.5 Hz,1H), 3.47 (ddd, J=12.5, 3.0, 3.0, 1H), 3.35 (m, 2H), 3.16 (m, 2H), 3.02(dd, J=13.8, 11.3 Hz, 1H), 2.93 (s, 3H), 1.96 (m, 2H), 1.81 (m, 1H),1.72 (m, 1H), 1.56 (m, 1H). MS m/z (rel intensity) 575 (12), 328 (M+23)⁺ (6), 288 (M−17) (100).

Example 15 Synthesis of Series F Compounds:(2R)-1-{2-[(3S)-Pyrrolidin-3-ylamino]-acetyl}-boroPro-OH (21) Step 1:(2R)-1-{2-[(3S)-1-tert-Butoxycarbonyl-pyrrolidin-3-ylamino]-acetyl}-boroPro-(1S,2S,3R,5S)-pinanediolester (20)

The protocol described above for the synthesis of 3B was followedemploying (3S)-3-amino-pyrrolidine-1-carboxylic acid tert-butyl ester inplace of cyclopentylamine. Compound 20 was obtained as an oil.

Step 2: (2R)-1-{2-[(3S)-Pyrrolidin-3-ylamino]-acetyl}-boroPro-OH (21)

The protocol described above for the N-Boc deprotection and pinanediolester deprotection of compound 12 was applied to 20. Compound 21 wasobtained as a white solid. 21-TFA salt ¹H-NMR (500 MHz, CD₃OD) δ 4.12(m, 3H), 3.76 (m, 1H), 3.54 (m, 3H), 3.41 (m, 2H), 3.26 (m, 1H), 2.55(m, 1H), 2.28 (m, 1H), 2.05 (m, 3H), 1.74 (m, 1H). MS m/z (relintensity) 241 (M) (27), 224 (100), 209 (73), 155 (47).

Example 16

Using the procedures illustrated above, the following compounds in theTable were prepared and characterized using liquid chromatography-massspectroscopy (LC-MS).

TABLE Compound No. Series Structure LC-MS 22 A

255 (M + 1) (13), 237 (100) 23 A

227 (M + 1) (10), 209 (100) 24 A

229 (M + 1) (18), 211 (100) 25 A

215 (M + 1) (12), 197 (100) 26 A

263 (M + 1) (5), 245 (100) 27 A

277 (M + 1) (4), 259 (100) 28 A

283 (M + 1) (22), 265 (100) 29 A

277 (M + 1) (5), 259 (100) 30 A

283 (M + 1) (21), 265 (100) 31 A

269 (M + 1) (16), 251 (100) 32 A

763 (6), 382 (M + 1) (100) 33 A

284 (M + 1) (19), 266 (100) 34 A

651 (28), 326 (M + 1) (57), 308 (100) 35 A

691 (22), 346 (M + 1) (100), 328 (86) 36 A

703 (28), 352 (M + 1) (18), 334 (100) 37 A

691 (49), 346 (M + 1) (14), 328 (100) 38 A

703 (27), 352 (M+ 1) (3), 334 (100) 39 A

651 (48), 326 (13), 308 (100) 40 A

382 (M+ 1) (100), 364 (7) 41 A

332 (M+ 1) (100), 314 (10) 42 A

531 (15), 266 (M − 17) (100) 43 A

271 (M + 1) (100), 253 (16) 44 A

270 (M + 1) (100), 252 (17) 45 A

731 (42), 366 (M + 1) (100), 348 (43) 46 A

791 (12), 396 (M + 1) 47 A

721 (10), 361 (M + 1) (100) 48 A

285 (M + 1) (100), 267 (12) 49 A

595 (48), 298 (M + 1) (100), 280 (80) 50 A

679 (29), 340 (100) 51 A

719 (92), 360 (M + 1) (65), 342 (100) 52 A

791 (35), 396 (M + 1) (100), 378 (14) 53 A

595 (89), 298 (M + 1) (44), 280 (100) 54 A

719 (72), 360 (M + 1) (40), 342 (100) 55 A

731 (100), 366 (M + 1) (34), 348 (86) 56 A

340 (M + 1) (5), 322 (100), 304 (18) 57 A

731 (100), 366 (M + 1) (52), 348 (94) 58 A

773 (33), 396 (M + 1) (100), 378 (16) 59 A

595 (93), 298 (M + 1) (26), 280 (100) 60 A

679 (100), 340 (98), 322 (70) 61 A

346 (M + 1) (100), 328 (12) 62 B

249 (M − 17) major, 267 (M + 1) minor 63 B

289 (M + 1) minor, 271 (M − 17) major 64 B

289 (M + 1) minor, 271 (M − 17) major 65 B

213 (M − 17), 425 (2 M + 1) 66 B

282 (M − 17) major 67

257 (M − 17) major, 275 (M + 1) minor 68 B

209 (M − 17) major, 227 (M + 1) minor 69 B

285 (M − 17) major, 303 (M + 1) minor 70 B

209 (M − 17) major, 227 (M + 1) minor 71 B

211 (M − 17) major, 229 (M + 1) minor 72 B

209 (M − 17) major, 227 (M + 1) minor 73 B

209 (M − 17) major, 227 (M + 1) minor 74 B

257 (M − 17) major, 275 (M + 1) minor 75 B

209 (M − 17) major, 227 (M + 1) minor 76 B

223 (M − 17) major, 241 (M + 1) minor 77 B

223 (M − 17) major, 241 (M + 1) minor 78 B

223 (M − 17) major, 241 (M + 1) minor 79 B

235 (M − 17) major, 253 (M + 1) minor 80 B

235 (M − 17) major, 253 (M + 1) minor 81 B

235 (M − 17) major, 253 (M + 1) minor 82 B

251 (M − 17) major, 269 (M + 1) minor 83 B

235 (M − 17) major, 253 (M + 1) minor 84 B

233 (M − 17) major, 251 (M + 1) minor 85 B

233 (M − 17) major, 251 (M + 1) minor 86 B

275 (M − 17) major, 293 (M + 1) minor 87 B

311 (M − 17) major, 329 (M + 1) minor 88 B

209 (M − 17) major, 227 (M + 1) minor 89 B

434 (M − 17) major 90 B

446 (M + 1) (23), 428 (100) 91 B

350 (M − 17) major, 368 (M + 1) minor 92 B

434 (M − 17) major 93 B

346 (M + 1) (100), 328 (14) 94 B

511 (9), 256 (M + 1) (100), 238 (19) 95 B

201 (M + 1) (100), 183 (22) 96 B

255 (M + 1) (100), 237 (100) 97 B

187 (M + 1) (5), 169 (100) 98 B

243 (M + 1) (5), 225 (71) 99 B

449 (5), 243 (M + 1) (7), 225 (100) 100 B

223 (M + 23) (3), 183 (48) 101 B

223 (M + 23) (4), 183 (10) 102 C

228 (M + 1) (55), 210 (M − 17) (95) 103 C

210 (M − 17) major, 228 (M + 1) minor 104 C

210 (M − 17) major, 228 (M + 1) minor 105 D

575 (12), 328 (M + 23) (6), 288 (100) 106 D

452 (M + 1) (3), 434 (100) 107 D

368 (M + 1) (2), 350 (100) 108 D

428 (M − 17) (100) 109 D

386 (M − 17) (100) 110 D

436 (M + 1) (10), 418 (100) 111 D

436 (M + 1) (4), 418 (100) 112 D

627 (25), 332 (M + 1) (10), 314 (100) 113 D

368 (M + 1) (38), 350 (100) 114 D

350 (M − 17) (100), 332 (22) 115 D

332 (M + 1) (4), 314 (93) 116 D

338 (M + 1) (3), 320 (98) 117 D

332 (M + 1) (27), 314 (100) 118 D

338 (M + 1) (21), 320 (100) 119 D

727 (8), 368 (M − 17) (56) 120 D

603 (24), 302 (M − 17) (73) 121 F

242 (M + 1) (100), 224 (19) 122 F

242 (M + 1) (100), 224 (9) 123 F

300 (M + 1) (11), 282 (100) 124 F

371 (M − 17) major, 389 (M + 1) minor 125 F

256 (M + 1) (100) 126 F

256 (M + 1) (100), 238 (8) 127 F

256 (M + 1) (100), 238 (10) 128 F

210 (M − 17) major, 228 (M + 1) minor 129 F

256 (M + 1) (100), 238 (10) 130 G

623 (28), 312 (M + 1) (100), 294 (30) 131 G

819 (20), 410 (100) 132 G

374 (M + 1) (100), 356 (67) 133 G

759 (57), 380 (M + 1) (100), 362 (64)

Example 17 Dependence of Aminoboronate and Boronic Acid Forms ofInventive Compounds on pH

A 0.4 M stock solution of Na₂HPO₄ was prepared by dissolving 909 mg ofsalt in 16 mL of D₂O. pH was adjusted to the desired value by dropwiseaddition of either 20% DCl in D₂O or 5% DCl in D₂O. The pH values weremeasured with a Fisher Scientific Accumet AB15 pH meter. Aliquots of thestock solution (4 mL) were prepared and 8 mg of compound 4 in the closedform (aminoboronate) were added to each one. The scintillation vialswere capped, sealed with parafilm and allowed to stand in the dark forthree days. After this time pH was measured again. The open/closed(i.e., linear/cyclic) ratio of compound 4 isomers at each pH wasdetermined by recording the corresponding ¹H-NMR spectra in a Varian AS500 MHz instrument and measuring the ratio of the integrals of the peaksat 2.90-2.95 ppm and 2.40-2.50 ppm characteristic of the open and closedforms, respectively. FIG. 1 shows that the closed form predominates athigher pHs such as physiological pH, whereas the open form predominatesat lower pHs.

Example 18

The final compounds of Examples 1-16 were tested in vitro as describedherein and each displayed an IC₅₀ or K_(i) of 10 μM or less.

While the invention has been described and exemplified in sufficientdetail for those skilled in this art to make and use it, variousalternatives, modifications, and improvements will be apparent to thoseskilled in the art without departing from the spirit and scope of theclaims.

All patents and publications are herein incorporated by reference to thesame extent as if each individual publication was specifically andindividually indicated to be incorporated by reference.

The invention illustratively described herein suitably may be practicedin the absence of any element or elements, limitation or limitationswhich is not specifically disclosed herein. Thus, for example, in eachinstance herein any of the terms “comprising”, “consisting essentiallyof and “consisting of may be replaced with either of the other twoterms. The terms and expressions which have been employed are used asterms of description and not of limitation, and there is no intentionthat in the use of such terms and expressions of excluding anyequivalents of the features shown and described or portions thereof, butit is recognized that various modifications are possible within thescope of the invention claimed. Thus, it should be understood thatalthough the present invention has been specifically disclosed bypreferred embodiments and optional features, modification and variationof the concepts herein disclosed may be resorted to by those skilled inthe art, and that such modifications and variations are considered to bewithin the scope of this invention as defined by the appended claims.

In addition, where features or aspects of the invention are described interms of Markush groups, those skilled in the art will recognize thatthe invention is also thereby described in terms of any individualmember or subgroup of members of the Markush group. For example, if X isdescribed as selected from the group consisting of bromine, chlorine,and iodine, claims for X being bromine and claims for X being bromineand chlorine are fully described.

Other embodiments are set forth within the following claims.

1-178. (canceled)
 179. A compound of formula (I):

including all cyclic isomers thereof, stereoisomers thereof, solvatesthereof, hydrates thereof and pharmaceutically acceptable salts thereof,wherein: n is 1 to 3; X is CH₂, CF₂ or C(CH₃)₂; Z is H, halogen,hydroxyl, (C₁₋₆)alkoxy, (C₁₋₁₂)alkyl, (C₃₋₁₂)cycloalkyl, phenyl, orheteroaryl; wherein the phenyl and heteroaryl groups are optionallymono- or independently plurisubstituted with R⁷; optionally, X togetherwith an adjacent ring carbon and Z form a fused cyclopropyl; optionally,one of the bonds in the ring containing X is a double bond; R⁷ ishalogen, (C₁₋₁₀)alkyl, (C₁₋₁₀)alkoxy, (C₁₋₁₀)alkylamino,(C₁₋₁₀)dialkylamino, benzyl, benzyloxy, hydroxy(C₁₋₆)alkyl,hydroxymethyl, nitro, trifluoromethyl, trifluoromethoxy,trifluoromethylthio, N-hydroxyamino, cyano, carboxy, acetamido, hydroxy,sulfamoyl, sulfonamido, or carbamoyl; R¹ and R² are each independently—OH, a hydroxyl bearing a boronic acid protecting group, or a groupcapable of being hydrolyzed to a hydroxyl group in an aqueous solutionat physiological pH or in biological fluids; R³, R⁴ and R⁵ are selectedfrom the following Set I or Set II; Set I: R³ and R⁴ independently arehydrogen, C₁ to C₆ alkyl or C₃ to C₆ cycloalkyl; and R⁵ is heteroaryl;cycloheteroalkyl or cycloheteroalkylalkyl; all optionally mono- orindependently plurisubstituted with halogen, alkyl, polyhaloalkyl,alkoxy, haloalkoxy, polyhaloalkoxy, alkoxycarbonyl, alkenyl, alkynyl,cycloalkyl, cycloalkylalkyl, polycycloalkyl, heteroarylamino, arylamino,cycloheteroalkyl, cycloheteroalkylalkyl, hydroxy, hydroxyalkyl, nitro,cyano, amino, substituted amino, alkylamino, dialkylamino, thiol,alkylthio, alkylcarbonyl, acyl, alkoxycarbonyl, aminocarbonyl,alkynylamino-carbonyl, alkylaminocarbonyl, alkenylaminocarbonyl,alkylcarbonyloxy, alkylcarbonylamino, arylcarbonylamino,alkylsulfonylamino, alkylaminocarbonyl-amino, alkoxycarbonylamino,alkylsulfonyl, aminosulfinyl, aminosulfonyl, alkylsulfinyl, orsulfonamido; or, Set II R³ and R⁴ are hydrogen and R⁵ is:

wherein R²⁰ is hydrogen, (C₁₋₈)alkyl, (C₁₋₆)alkylcarbonyl, mono- ordi-(C₁₋₆)alkylaminocarbonyl, (C₃₋₈)cycloalkylcarbonyl, benzyl, benzoyl,(C₁₋₆)alkyloxycarbonyl, aralkyloxycarbonyl, pyridinyl, pyrimidinyl,phenyl, phenyl-substituted thiazolyl, phenylaminocarbonyl,alkylsulfonyl, or phenylsulfonyl; wherein the benzyl, benzoyl,pyridinyl, pyrimidinyl, phenyl, phenylaminocarbonyl, alkylsulfonyl, andphenylsulfonyl groups are optionally mono- or independentlydi-substituted with R¹²; R¹² is halogen, trifluoromethyl, cyano, nitro,(C₁₋₆)alkyl, (C₁₋₆)alkoxy, cycloalkyl, carboxy, acetamido, hydroxy,hydroxy(C₁₋₆)alkyl, trifluoromethoxy, sulfamoyl, carbamoyl, sulfonamido,alkylsufonyl, phenylsulfonyl, aryl, or heteroaryl; wherein the aryl andheteroaryl groups are optionally mono- or independently plurisubstitutedwith R⁷; R_(x) is hydrogen, (C₁₋₈)alkyl, (C₃₋₁₂)cycloalkyl, benzyl, orphenyl; wherein the benzyl and phenyl groups are optionally mono- orindependently di-substituted on the ring with R¹²; R_(y) is absent or ishalogen, (C₁₋₈)alkyl, (C₁₋₈)alkoxy, O-alkylcarboxylate,O-aralkylcarboxylate, N-alkylcarboxamido, N-aralkylcarboxamido, orphenyl; s is 1 to 6; t is 0 to 6; and u is 0 to 3; and wherein a bondbisected by a wavy line signifies a point of attachment.
 180. A compoundof claim 179 wherein R¹ and R² are each hydroxyl.
 181. A compound ofclaim 179 wherein R¹ and R² are each hydroxyl that independently ortogether bear a boronic acid protecting group formed from(+)-pinanediol; pinacol; 1,2-dicyclohexyl-ethanediol; 1,2-ethanediol;2,2-diethanolamine; 1,3-propanediol; 2,3-butanediol, diisopropyltartrate; 1,4-butanediol; diisopropylethanediol; (S,S,)-5,6-decanediol;1,1,2-triphenyl-1,2-ethanediol;(2R,3R)-1,4-dimethyoxy-1,1,4,4-tetraphenyl-2,3-butanediol; methanol;ethanol; isopropanol; catechol; or 1-butanol; or wherein R¹ and R²independently or together are a group capable of being hydrolyzed toform a boronic acid group —B(OH)₂ in an aqueous solution atphysiological pH or in biological fluids.
 182. A compound of claim 179wherein X is CH₂; the ring containing X is saturated; R¹ and R² are eachhydroxyl, R³ and R⁴ are hydrogen; and R⁵ is a group of Set I.
 183. Acompound of claim 179 wherein X is CH₂; the ring containing X issaturated; R¹ and R² are each hydroxyl, R³ and R⁴ are hydrogen; and R⁵is a group of Set II.
 184. The compound of claim 179 wherein X is CH₂;the ring containing X is saturated; R¹ and R² are hydroxyl, R³ and R⁴are hydrogen; and R⁵ is a group of formula


185. The compound of claim 184 wherein R_(x) is hydrogen.
 186. Thecompound of claim 184 wherein R²⁰ is hydrogen.
 187. A pharmaceuticalcomposition comprising a compound of claim 179 and a pharmaceuticallyacceptable carrier.
 188. A method for inhibiting dipeptidyl peptidase-IVcomprising contacting dipeptidyl peptidase-IV with an effective amountof a compound of claim 179 or of the composition of claim
 187. 189. Amethod according to claim 188, wherein the dipeptidyl peptidase-IV iswithin a mammal in need of treatment for a malcondition that can beregulated or normalized via inhibition of dipeptidyl peptidase-IV andthe contacting step comprises administering to the mammal atherapeutically effective amount of the compound.
 190. A methodaccording to claim 189 wherein the malcondition is impaired glycemiccontrol or the malcondition is diabetes.
 191. A method for inhibitingdipeptidyl peptidase-IV according to claim 190 wherein the compoundselectively inhibits dipeptidyl peptidase-IV over at least one otherdipeptidyl peptidase.
 192. The method of claim 188 further comprisingadministering a therapeutically effective amount of a second medicamentselected from the group consisting of a second medicament that increasesinsulin secretion, increases insulin sensitivity, reduces the uptake ofsugar from the gastrointestinal tract, enhances the effect of endogenouspeptides or proteins that affect glycemic control, or provides areplacement for endogenous peptides, proteins that affect glycemiccontrol, or any combination thereof.
 193. A method according to claim192 wherein one or more second medicaments are administered and areselected from the group consisting of a) Other dipeptidyl peptidase-IVinhibitors; b) Insulin sensitizers selected from the group consisting of(i) PPAR agonists, (ii) biguanides, and (iii) protein phosphatase-1Binhibitors; c) Insulin or insulin mimetics; d) Sulfonylureas or otherinsulin secretagogues; e) α-glucosidase inhibitors; f) glucagonsreceptor agonists; g) GLP-1, GLP-1 mimetics, and GLP-1 receptoragonists; h) GLP-2, GLP-2 mimetics, and GLP-2 receptor agonists; i) GIP,GIP mimetics, and GIP receptor agonists; j) PACAP, PACAP mimetics, andPACAP receptor 3 agonists; k) Cholesterol lowering agents selected fromthe group consisting of (i) HMG-CoA reductase inhibitors, (ii)sequestrants, (iii) nicotinyl alcohol, nicotinic acid or a salt thereof,(iv) PPARα agonists, (v) PPARα/γ dual agonists, (vi) inhibitors ofcholesterol absorption, (vii) acyl CoA: cholesterol acyltransferaseinhibitors, and (viii) anti-oxidants; l) PPARδ agonists; m) Anti-obesitycompounds; n) An ileal bile acid transporter inhibitor; o)Anti-inflammatory agents; p) G-CSF, G-CSF mimetics, and G-CSF receptoragonists; and q) EPO, EPO mimetics, and EPO receptor agonists.
 194. Apharmaceutical combination comprising a compound of claim 179; and asecond medicament that increases insulin secretion, increases insulinsensitivity, reduces the uptake of sugar from the gastrointestinaltrack, enhances the effect of endogenous peptides or proteins thataffect glycemic control, provides a replacement for endogenous peptidesor proteins that affect glycemic control, or any combination thereof.195. The pharmaceutical combination of claim 194, wherein the secondmedicament is glyburide, glipizide, nateglinide, repaglinide, metformin,pioglitazone, rosiglitazone, acarbose, miglitol, exenatide, insulin,metformin, glyburide, glimepiride, glipyride, glipizide, chlorpropamide,gliclazide, acarbose, miglitol, pioglitazone, troglitazone,rosiglitazone, insulin, G1 -262570, isaglitazone, JTT-501, NN-2344,L895645, YM-440, R-119702, AJ9677, repaglinide, nateglinide, KAD1129,APR-H039242, GW-409544, KRP297, AC2993, LY307161, NN2211, or LY315902 orany combination thereof.
 196. The pharmaceutical combination of claim194 wherein the second medicament is suitable for treatment of adiabetes-associated condition.
 197. A pharmaceutical combinationaccording to claim 194 wherein the second medicament is an antidiabeticagent.
 198. A pharmaceutical combination according to claim 197 whereinthe weight ratio of the compound and the antidiabetic agent is fromabout 0.01:1 to about 100:1.
 199. The pharmaceutical combination ofclaim 194 wherein the second medicament is suitable for treatment of adiabetes-associated condition and the compound is present in a weightratio to the second medicament from about 0.01:1 to about 100:1.